TW568786B - A combination, pharmaceutical formulation, and kit for use in the treatment of affective disorders - Google Patents

Abstract

The invention relates to a combination of a first component (a) which is a selective 5-HT1A receptor antagonist having the formula I wherein R1 is n-propyl or cyclobutyl, R2 is isopropyl, tertiary butyl, cyclobutyl, cyclopentyl or cyclohexyl, R3 is hydrogen and R4 is hydrogen or methyl and being in the (R)-enantiomer form, with a second component (b) which is a selective h5-HT1B antagonist or partial agonist having the formula II wherein X is CH2, O, Y is CONH, NHCO, R1 is H, C1-C6 alky, C3-C6 cycloalkyl, R2 is H, C1-C6 alkyl, C1-C6 alkoxy, halogen, R3 is R4 and R5 independently are H or C1-C4 alkyl as racemate, R-enantiomer or S-enantiomer, and said components (a) and (b) being in the form of free bases, solvates or pharmaceutically acceptable salts thereof, the preparation thereof, pharmaceutical formulations containing said combination, use of and method of treatment of affective disorders such as depression, anxiety and OCD with said combination as well as a kit containing said combination.

Description

568786 A7 B7 V. Description of the invention (via the Central Standards Bureau of the Ministry of Industry and Technology, Consumer Cooperative Press f 1 The present invention is related to the inclusion of a selective 5-HTi A receptor antagonist, more specifically, carbamate-8 · fluoro-3-N, N-disubstituted-amino-3,4-dihydro-2H-1 benzopyran, and a selective h5_HTiB receptor antagonist or partial agonist 'more specifically via hexaoxopyryl or hexahydropyridine The product is a combination of tetrachloronaphthalene or 3,4_dihydro_2H-1_benzopyran derivatives substituted with each group, wherein each component is in the form of a free base, a solvate or a pharmaceutically acceptable salt thereof. The invention also relates to a method for preparing the combination of the present invention, which comprises a combination medicine, a formulation and the combination for the purpose of improving the treatment of emotional disorders such as depression, anxiety, obsessive-compulsive disorder, and obsessive-compulsive behavior disorder (OCD). , Etc .. With a clear background, current antidepressants usually take 2 to 4 weeks to achieve their full clinical effect. On the contrary, the side effects appear immediately. Therefore, the slower-acting depressants will make patients There is a fragile period of experience side effects, but not obtained The medical effect of the substance. The treating physician must often persuade the patient to continue the treatment during this period. In addition, due to the gradual rate of onset of action, the suicidal patient may have suicide motivation again before he completely reverses the symptoms, leading him Suicide towards the mouth, and often require hospitalization, antidepressants that begin to act quickly are not only beneficial due to the rapid reduction of symptoms, but also more easily accepted by patients and physicians, and reduce the need and time for hospitalization. To treat other emotional disorders such as ·· For anxiety and 0CD, it takes the same time to achieve full clinical results. (Please read the precautions on the back before filling this page)

-4- 786786 A7 B7 V. Description of the invention (3 Selective h5-HT1B antagonist or partial agonist

Y

3 R 丨 丨 丨: ----- # 11 (Please read the notes on the back and then fill out this page) (II) where X is CH2, ο; Υ is CONH, NHCO;

Ri is H, Ci-C6fe group, (113- (1; 6 ring alkyl group; R2 is fluorene, C "C6 alkyl group, alkoxy group, halogen; R3 is -N 0 -C (0) -N 〇 4

〇 一 CF3 — c (〇) nr4r5; The R4 and R5 of the Consumer Cooperatives of the Central Standards Bureau of Didi Ministry are R Η or CVC 4 alkyl, respectively, which are racemates, R-enantiomers or S-pairs. Enantiomers, and the components 0) and (b) are free, solvates (preferably hydrates), or their pharmaceutically acceptable salt forms, the effect of this combination starts quickly, and the results are provided More effective treatment for patients. In the combination of the present invention, the following 5-HT i A bracketing agents can be used as a component ^) -6 The paper size is applicable to the Chinese National Standard (CNS) A4 specification (210X297 mm) 568786 A7 ----_ ____ V. Invention Explanation (4) (R > 3 < N-Cyclopentyl · N-n-propylamino) -8-fluoro-5 · methylaminomethylmethyl-3,4-dihydro-2H-1-phenylpyran , (R) 8 rat-isopropyl-n-propylamino) -5-aminomethylamino · 3,4 · dihydro · 2Η-1-phenylpyranin, (R) _5_aminomethylpyridine · 3_ ( Ν-third butyl-N • n-propylamino) _8-fluoro-3,4-dihydro-2Η_1-benzylpyran, (R) · 5 · aminomethyl-3--3- (Ν, Ν- 二Cyclobutylamino) -8-fluoro · 3,4-dihydro-2Η_1-benzenexanthenan, (R) -5-aminomethylamidino_3_ (fluorenecyclobutyl-N-propylamino) · 8- Fluoro-3,4-dihydro-2 Η -1 -Feng 幷 phanan, (R) -5-Aminomethyl · 3_ (N-cyclobutyl-N-isopropylamino) -8-fluoro · 3,4_dihydro-2Η-1-phenylpyran, (R) -5-aminomethylmethyl-cyclopentyl-N-n-propylamino) -8-fluoro-3,4-dihydro-2 Η _ 1 -Benzo-pyran, (R) _5-Aminomethyl- 3-(N-cyclohexyl-N-n-propylamino) _8_fluoro · 3,4-dihydro-2 Η -1 -benzene Benzodipyran, (R) -5-aminomethylmethyl-3βι (N-cyclopentyl- -Cyclobutylamine) -8 -Fluoro- 3,4-dihydro-2 Η · 1 -Benzene p-pyran, printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Distillation (Please read the notes on the back before filling in (This page) This article discloses (R) -5-aminomethyldonyl-8-fluoro-3-N, N-disubstituted-amino groups. 3,4-dihydro-2fluorene-1-benzopyrrolidine Illustrated in WO 95/11891 (PCT / SE94 / 01010) 〇 (R) -5_Aminomethylamidinofluoro-3_N, N-disubstituted amino-3,4_dihydro-2Η-1 -phenylpyridine The ranes are free base, solvates (preferably hydrates), or pharmaceutically acceptable salts. Both organic and inorganic acids can be used and the paper size of this paper is applicable to Chinese National Standard (CNS) A4 specification (210X 297 mm) 568786 Printed by the Consumers Cooperative of the Central Bureau of Standards of the Ministry of Distillation A7 B7 V. Description of the invention (5) The compound forms a non-toxic pharmaceutically acceptable acid addition salt. Examples of acids are sulfuric acid, nitric acid, osmic acid, oxalic acid, hydrochloric acid, formic acid, hydrobromic acid, citric acid, acetic acid, lactic acid, tartaric acid, dibenzoyltartaric acid, diethyltartaric acid, dihydroxyarsolic acid, ethanedisulfonic acid, Aminosulfonic acid, succinic acid, propionic acid, glycolic acid, malic acid, gluconic acid, pyruvic acid, phenylacetic acid, 4-aminobenzoic acid, alanine, salicylic acid, 4-aminosalicylic acid, 4 -Hydroxybenzoic acid, 3,4-dihydroxybenzoic acid, 3,5-dihydroxybenzoic acid, 3-hydroxy-2 · acetic acid, nicotinic acid, methanesulfonic acid, ethanesulfonic acid, isethionic acid, benzenesulfonic acid Acids, p-toluenesulfonic acid, sulfanilic acid, sulfamic acid, ascorbic acid, cyclohexylaminesulfonic acid, fumaric acid, maleic acid and benzoic acid. These salts are easily prepared by methods known in the relevant art. Specificity of these (R) -5-aminomethylamino-8-fluoro · 3 · N, N disubstituted amino groups_3,4-dihydro-2Η · 1-benzopyrans to the 5_ΗΤια receptors in CNS The sexual subfamily has a high affinity and acts as an antagonist on the 5-HT1A receptor, and exhibits sufficient bioavailability after oral administration. In other preferred embodiments, the second component (b) is a compound in which X is CH2 in the formula (η), and a compound in which γ is NHCO in the formula, and a compound of R3 morphinyl in the formula . Preferred are compounds wherein hydrogen, methyl or ethyl are used in the formula and R2 is hydrogen, methyl, ethyl, fluorenyl or bromo. A preferred compound such as formula II is: (R) -N- [8- (hexahydropyridine_ ^ yl) _1,2,3,4_tetrahydro_2_amidinomorpholine benzamidine; (R) -N- [8_ (4_Ethylhexahydropyridine-1_yl) _1,2,3,4β > tetrapyrene_2_fluorenyl] _4_ morphazimide; (R) N- [8_ (4-methyl: rc hydrogen p ratio. Well_ι_yl) _1,2,3,4-tetrahydro-2-fluorenyl] -4 · »(Please read the precautions on the back before filling this page )

, 1T Φ.

568786 A7 B7 V. Description of the invention (6) Morpholine benzamidine; (R) -N- [5 -methoxy-8- (4-methylhexahydrowell-1-yl) -1,2,3, 4-tetrahydro-2-fluorenyl] _4-morpholinobenzamide; (R) -N- [5 · ethyl_8 · (4-methylhexahydropyridin-1-yl) -1,2 , 3,4 · Tetrahydro-2-fluorenyl] -4 -morpholinyl amine; (R) -N- [5 · ethyl-8_ (4-methylhexahydropyridine_1_yl) 1,2,3,4_tetrahydro-2-fluorenyl]-(4-morpholinecarbonyl) benzidine; (11) -fluorene [5-methoxy-8- (4-methylhexahydropyridine) Phen-1-yl) -1,2,3,4-tetrahydro_2-stubyl] -4-morpholinecarbonylbenzamide; (R) -N- [5_bromo-8- (hexahydropyridine) Phen-1-yl) -1,2,3,4-tetrahydro-2-fluorenyl] -4-morpholinobenzamide; N- [5 -bromo-8- (4-methylhexahydroxide) Mizuki-1-yl) -1,2,3,4-tetrahydro-2-fluorenyl] -4-morphazine; (R) -N- [5-bromo-8- (4-methyl Hexahydropyridine-1 · yl) 1,2,3,4-tetrahydro-2-fluorenyl] _4-trifluoromethylbenzidine; (R) -N- [5-methyl_8 · (4_methylhexahydropyridine-1 · yl) -1,2,3,4-tetrahydro-2-stilbyl] -4-morpholine benzidine; printed by the Consumers' Cooperative of the Central Bureau of Standards (Please read the precautions on the back before filling out this page) Ν- (4 -morphonyl) -8- (4- (Methyl hexazine ρ bihexyl) -5 -methoxy-1,2,3,4-tetrahydrofluoren-2-amine; (r) -N_ (4-morpholinyl) -8_ ( 4-methylhexahydropyridyl) _5_methoxy-1,2,3,4-tetrahydrofluorene-2-carboxamidine; (S) _N- (4-morpholinyl) -8- (4-methylhexahydropyridyl) · 5-methoxy-1,2,3,4-tetrahydropyrene-2-amine 1 &amine; (R) -N-(? 4-carboxyphenyl) -8- (4-methylhexahydropyridine-1-yl) -5-methoxy · -9- This paper size applies to Chinese National Standard (CNS) A4 specification (210X 297 mm) A7 B7 V. Invention Explanation (7) 1,2,3,4-Tetrahydrofluorene-2-carboxamide; (Please read the note-notes on the back before filling this page) (S) -N- [S- (4-甲Chiral point chlorhex-1-yl) -3,4-diazine-2H-1-phenylpyridine π pyran · 3-yl] -4-morpholinobenzine; (S) -N- [S- (4 · methyl 7T -yl) _3,4-dichloro-2H_1_benzopyridin-2-yl] _4_ (4 · hexahydropyridone-1 · yl) benzidine; (S) -N -[8 -Methyl-5- (4-methylhydrogen ρ than Mizuki-1-yl) _3,4_dihydro_2H-1-phenyl hydrazino-3 -yl] -4- (dimethylform Amine post group) amine benzoate;

Kf- [4- (4-Moryl) phenyl] -8-methoxy · 5- (4 • methyl-hexachloro p-ratio-1-yl) -3,4 -diaza-2Η -1-Benzamidine π-Bran-3-Betamine. Particularly preferred compounds are: (feet) -1 ^-[8- (4-methylhexahydro port ratio 17 well-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -4 -Morphylamine, (R) -N- [5-methoxy-8- (4-methylhexahydro u ratio ρ Well-1-yl) -1,2,3,4-tetrahydro- 2-naphthyl] -4-morph-4-benzimidamine, and (R) -N- [5-methyl-8- (4-methylhexahydrop-support ^ 1-yl) -1,2,3 , 4-tetrahydro_2-fluorenyl] -4-morpholinobenzamide. Compounds of the formula η in the form of (R) -enantiomers, (S) -enantiomers or racemates can be free bases or pharmaceutically acceptable salts or solvates thereof, for example: the central standard of water through the dripping department Bureau employees consume cooperatives. Herein, the Ci-C6 alkyl group may be linear or branched. Ci-C6 alkyl may be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, second butyl, third butyl, n-pentyl, isopentyl, third pentyl Base, neopentyl, n-hexyl or isohexyl, C1-C4 alkyl is preferred, and methyl and ethyl are preferred. In this article, C "C4 radicals can be straight or branched. C ^ C: 4 radicals can be -10-i paper size & Chinese National Standard (CNS) A4 specification (210-X 297)." *-568786 A7 B7 V. Description of the invention (8) Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, second butyl or dibutyl; tributyl. Ethyl is preferred. In this context, CyC6 cycloalkyl may be cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. In this context, 'Ci-C6 alkoxy may be straight or branched. Ci-C ^ The oxy group may be a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group, an n-butoxy group, a butanyl group, a first butyl lactyl group, a second butoxy group, an n-pentyloxy group, iso As the pentyloxy group, the third pentyloxy group, the neopentyloxy group, the n-hexyloxy group, or the isohexyloxy group, an alkoxy group is preferred, and a methoxy group is particularly preferred. Herein, the halogen may be fluorine, gas, bromine, or Iodine, of which bromine is preferred. The combination according to the present invention may be a pharmaceutical formulation comprising both the first active ingredient (a) and the first active ingredient (b), or two different pharmaceutical formulations, one Contains the first active ingredient ( a), the other contains the second active ingredient (b). The pharmaceutical formulation may be in the form of tablets or capsules, powders, mixtures, solutions, etc., or other suitable pharmaceutical formulations. The combination of the present invention is prepared by adding methods such as The selective 5_HT1A antagonist defined above is in the same formulation as the selective h5_HTiB antagonist defined above, for example; it is mixed in a conventional manner. The present invention is also printed by the Consumers Cooperative of the Central Standards Bureau of the Ministry of Education. Includes a method to improve the onset of healing

A combination containing the first component (a) (which is a selective 5-HTi A antagonist as defined above) and the second component (b) (which is a selective h5-_ht1b antagonist as defined above) is administered at time. Another specific embodiment of the present invention is a kit comprising a first component (a) (which is a selective 5-HTia antagonist as defined above) and a second _ -11-568786 A7 ___B7 '--- --------______ 5. The combination of invention description (9) and ingredient (b) (which is a selective h5-HT1B antagonist as defined above). The set; the set may include instructions for use. θ1 Drug Formulations According to the present invention, the compounds in the combination can usually be administered orally, rectally or by injection, which is administered in the form of a pharmaceutical formulation containing an active ingredient, which is in the form of a free base, a solvate (for example: Hydrate) or pharmaceutically acceptable non-toxic acid addition salts, such as: hydrochloride, hydrobromide, lactate, acetate, phosphate, sulfate, sulfamate, citric acid, tartrate , Oxalate, etc., in a pharmaceutically acceptable dosage form: The dosage form can be a solid, semi-solid or liquid formulation. Usually, the active ingredient two accounts for 0.05 to 99% by weight of the formulation, more specifically it accounts for 5 to 20% by weight of the formulation for injection and 0.02 to 50% by weight of the composition for oral use. Printed by the Consumer Standards Cooperative of the Central Bureau of Standards (please read the note at the back of the page • Implementation #Fill this page ”Pharmaceutical formulations contain active ingredients, and can be supplemented with adjuvants, diluents, excipients and / or inert carriers as needed Combination. When manufacturing a pharmaceutical formulation of the combination of the present invention in an oral unit dosage form, selected compounds and solid excipients ^ such as: lactose, sucrose, sorbitol, mannitol, starches such as: potato starch, Corn starch or amylopectin, cellulose derivatives, binding agents such as gelatin or polyvinylpyrrolidone, disintegrating agents such as sodium starch glycolate, cross-linked PVP, cross-linked methyl cellulose sodium and lubricants such as: Mix magnesium stearate, stearic acid, polyethylene glycol, bad, stone bug, etc., and then press into a bond. If you need to coat the drug key, you can use for example: gum arabic, gelatin, talc Coatings of concentrated sugar solutions such as sulphur dioxide, dioxin, etc. can be made as described above; polymer coated tablets known in the art are available; q polymers are soluble in easily volatile organic solvents or Organic solvent mix-12- This paper rule Yun Yun Cai Guan Jia standards (publication c ^ T ^ J7_21GX297 1 A7 B7 Ministry of Economic Affairs Bureau Standards Bureau staff consumer cooperatives printed meals 568786-V. invention description (10 dyes can be added to these coatings, so that It is easy to distinguish between lozenges containing different active substances or different amounts of active compounds. Withered capsules, the active substances can be mixed. For example: vegetable oil or polyethanol capsules can contain active substance particles. Agents, such as: lactose, sugar, sorbitol, mannitol, starch (for example: 7 tapioca starch, corn starch or amylopectin), cellulose derivatives or gelatin. Can also be in hard gelatin capsules Filled with liquid or semi-solid drugs. The unit dosage form for rectal administration can be a solution or suspension, or can be made in the form of a suppository, which contains the active substance in a neutral lipid mixture, or made into a rectal capsule, which The active substance is mixed in vegetable oil or paraffin oil. Liquid formulations for oral use can be in the form of a syrup or suspension, for example: a solution containing about Q 2 to about 20% by weight of the active substance described herein, The rest are chewing sugar, and "a mixture of ethanol, water, glycerol, and propylene glycol. These liquid formulations may optionally include colorants, flavors, saccharin, and carboxymethyl cellulose as a conditioner or other known to those skilled in the art Excipient parenteral solutions for injection can be prepared from the water-soluble pharmaceutically acceptable salt of the active substance as an aqueous solution, preferably at a concentration of about 0.05 to about weight percent. These solutions may also contain & And / or buffering agents and are preferably provided in various unit dose ampoules. A suitable daily dose of the active compound in the combination of the present invention for treating the human body is about 0.01 to 100 mg / kg body weight per oral administration, and Administered finely from 0. 00 i to mg / kg body weight. The daily dose of active h5_HTiB can be very different from the daily dose of 5-ΗΤΑΑ antagonist, but the dose of these two active compounds It can be the same. 13- This paper size applies to China National Standards (CNS) A4 (21〇χ297297) (Please read the precautions on the back before filling this page)

568786 A7 V. Description of the invention (n Printed by the Consumer Cooperatives of the Central Bureau of Medicine of the Ministry of Medicine and Pharmacy --------- Ψ — (Please read the notes on the back before filling out this page) Another of the invention The aspect provides a combination usage, the first component ") of which is a selective 5-HTia antagonist of formula I as defined herein and the second component (b) is a selective pi-selective h5-HTiB antagonist or part thereof as defined herein An agonist, preferably an antagonist, and its use in the treatment of diseases that are regulated by 5-hydroxytryptamine (eg, emotional disorders). Examples of emotional disorders are CNS disorders such as: emotional disorders (depression, major depressive disorders) Seizures, bad moods, seasonal affective disorders, depressive periods of bipolar disorders), anxiety disorders (compulsive ideas and behaviors, presence or absence of empty-room panic, social panic, panic disorder of specific panic, generalized anxiety disorder, Post-traumatic stress disorder), personality disorder (impulsive control disorder, plucking mania), other CNS diseases such as: obesity anorexia, bulimia, premenstrual syndrome, sexual disorder, alcoholism, tobacco addiction, autism, Lack of willpower, hyperactivity, migraine, memory impairment (age-related memory impairment, presenile and senile dementia), pathological aggression, schizophrenia, internal knife / bioxing (e.g., blood stress Lactin hyperthyroidism), stroke, dyskinesia, Parkinson's disease, temperature regulation, pain, hypertension, etc. can also be treated with the composition described herein. Examples of other conditions regulated by serotonin are urinary incontinence, vasospasm , And tumor growth control (eg, lung cancer), and can also use the combination treatment described herein. Preparation of intermediates 1. When Y is NHCO and X is CH2 or 0. (i) by the compound of formula XXX VI Rotates or enantiomers-14- This paper size is in accordance with Chinese National Standard (CNS) A4 (210X29? Mm) Printed by the Consumers Cooperative of the Central Standards Bureau of Didi Ministry 568786 V. Description of the invention (12

: Appropriate; base-forming agents (such as di- or activated alcohols, for example, fufang, stinky, or stilbene-based κ produced by benzyl mesylate or benzyl tosylate) into a compound of formula 111. This reaction can use the compound ==, using agents such as: N, N • dimethylformamidine, acetone or acetonitrile: test examples: N_, NaHC () 3, K2C () 3 or trisamine, diethyl Amine is carried out in a temperature range of + 200c to + 150 ° F. Contains appropriate catalysts (such as iodinated or broken steel) to increase the reaction speed. The nitrogen of the compound XXX VI can also be protected. It is in the presence of reducing agents such as: cyanoborohydride, sodium, and sodium borohydride, for reductive alkylation with aryl aldehydes, or with hydrazone 2 and containing A suitable catalyst for palladium, platinum, germanium or nickel is catalytically reduced in a suitable solvent such as tetrahydrofuran, dioxolane, methanol or ethanol. Proton donors such as: p-toluenesulfonic acid can be used to catalyze the formation of imines / enamines, and the pH can be adjusted to slightly acidic with an appropriate acid such as acetic acid, which can accelerate the reaction to produce compound III. (ii) Demethylation reaction of compound of formula III to obtain compound of formula IV

Ν- (Βπ), 15- The size of this paper is applicable to Chinese National Standard (CNS) Α4 (210 × 297 mm)

568786 Α7 Β7 V. Description of the invention (13, it is based on the compound in a suitable solvent, acidic reagents such as: aqueous HBr, m, HBr / CH3C00H, BBr3, Alcl3 "than bite_hci or via alkali f nucleophile Such as: cheats- or treatment. A suitable solvent can be dichloromethane or chloroform and the reaction can be performed between -78 to +60 τ. (Iii) Conversion from a compound of formula IV to a compound of formula ν

η) 2 R:

-R (IV) which can react with the compound of formula VI 〇 NH2 (V) printed by the Consumer Standards Cooperative of the Central Bureau of Standards 〇

Wherein L represents a leaving group, for example: from a compound such as 翕 u I such as lice, bromine or iodine or an alkyl- or aryl-continyloxy group, such as p-phenylene and SS-oxyl group, and R a Or a low-carbon alkyl group, such as: methyl. The method can be carried out using a compound of formula IV and a base such as: K2C03, Na2C03, KOH, NaOH, B11T; a salt obtained by the reaction of BuLl or NaH. This reaction can be promoted in a suitable solvent, such as: aprotic -16 This paper size applies to China National Standard (CNS) Α4 size (210X297 mm) (Please read the precautions on the back before filling this page)

568786 A7 B7 V. Description of the invention (14 Solvents such as: dioxolane, N, N-dimethylformamide, tetrahydrofuran, toluene, benzene or petroleum ether, and the reaction can be performed at +20 ° C to Between + 15 ° C. (Iv) recombination of a compound of formula V to a compound of formula VII

fN- (Bn) 2

, ΝΗ, 〇Η (Please read the notes on the back before filling this page) Φ Printed by the Consumer Standards Cooperative of the Ministry of Standards (VII) It can be used in suitable solvents, such as aprotic solvents such as ζ Ν, N-dimethylformamide, dioxolane, 1,1,3,3 · tetramethylurea, tetrahydrofuran or trimethylamine hexamethyl phosphate, using a suitable base, for example: K2C03, K Rhenium, tertiary butanol, or NaH is performed at a temperature between +20 ° C and +150 ° C. When the solvent contains a suitable concentration of a co-solvent such as: 1,3-dimethyl-3,4,5,6-tetrahydro-2_ (1H) -pyrimidinone or hexamethylphosphonium triammonium phosphate, the reaction speed can be increased. (v) hydrolysis of a compound of formula VII to compound VIII, which can be carried out under acidic conditions using an acid such as: 504, HC1, or HBr in a suitable solvent, such as H2O, ethanol, methanol, or a mixture, and The reaction can be carried out between + 20 ° C and + 100X :, or under basic conditions, using a base such as: ν & 〇η or KOH, in a suitable solvent such as: ο, ethanol, methanol or a mixture thereof And the reaction can be performed between +20 ° C and 100X :. (vO is converted from a compound of formula VIII to a compound of formula IX. Standards for this paper (# 568786 A7 B7) 5. Description of the invention (------ 15

N-R

(VIII § by a) reacting with a compound of formula X

〇 Printing policy (X) of the Consumer Standards Cooperative of the Central Standards Bureau of the Ministry of Economics, where Ri is Ci-C6 alkyl or Cs-C6 cycloalkyl. The method can be used in a suitable solvent, for example, aprotic / anhydrous solvents such as tetrahydrofuran or N, N · dimethylformamide, and coupling agents such as: N, N, · carbonyl diweiwei It is carried out in the presence of, and the reaction temperature can be between +20 ° C and + 13〇 ^. After the reaction, a reduction reaction is carried out from an imine and a suitable reducing agent (for example: UA1H4) in a suitable solvent (for example: diethyl ether or tetrahydrofuran) at a temperature between +20 t and reflux, or b) with formula XI Compound reaction -_— ______ -18-This paper size applies Chinese national standard (cm) 〇χ 29: ^ y (please read the original meaning on the back before filling this page)

568786 A7 ^ ____ B7 V. Description of Invention (16) " ~ "

L

L (XI) where L represents a leaving group, for example: from a prime such as: chlorine or bromine or an alkane- or arylfluorenyloxy such as: p-toluenesulfonyloxy, and 1 is fluorene, C] -C6-alkyl or C3_C6-cycloalkyl. This method can be performed in a suitable solvent, such as ethanol, butanol, N, N-dimethylformamide, acetonitrile, or a mixture of water and acetonitrile, using a suitable test such as K2CO3, NaHC0, or KOH, and The reaction temperature can be between + 2 ° C and + 150 / C. Compounds of formula IX, where R1 is hydrogen, are converted to alkylated compounds of formula IX, where Ri is Ci-C ^ alkyl or the reaction can be suitably alkylated Agents such as: R ^ l, where L is a suitable leaving group, for example: halogen, such as: gas, bromine, or iodine or alkane- or arylsulfonyloxy group such as: p-toluenesulfonyloxy group, and R! The reaction is in a suitable solvent, such as N, N-dimethylformamide, acetone, acetonitrile or tetrahydrofuran, using a suitable base such as K2C03, NaHCOg, NaOH or trialkylamine such as triethylamine. The reaction can be carried out at a temperature of +20 ° C to + 120 C, or from a compound of formula IX, where Ri is hydrogen, is converted to an alkylated compound of formula IX, where Ri is C, C6 alkyl or CrC6 cycloalkane Group, which is related to compound Ri-CHO, where Ri is hydrogen or Ci-C5: fe group, or with C3-C6 cyclic ketone, in reducing agents such as: sodium cyanoborohydride, sodium cyanoborohydride Under reduced alkylation reaction, or with I and suitable catalysts containing palladium, platinum, rhodium or nickel, at -19- this paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm) I! I- --- Φ! (Please read the precautions on the back before filling in this page. J. Ordering by the Central Department of Consumer Affairs Cooperatives of the Department of Divination Printing 568786 A7 B7 Printing of the Central Government Bureau of Consumer Affairs of the Divise Department of Printing Cooperative Water 5. Description of the invention (17 A suitable solvent such as: tetrahydrooctane, dioxolane, methanol or ethanol for catalytic exogenous reactions. Proton donors such as p-toluenesulfonic acid can be used to catalyze the formation of imines / enamines. An appropriate acid such as acetic acid can be used to adjust the pH to slightly acidic to accelerate the reaction. (Vii) A compound of formula IX is halogenated, the center of which is hydrogen, (VC6 alkyl or C3-C6 cyclofluorenyl) to obtain a compound of formula XII

(ix) (χιΐ) It can be used for aromatic electrophilic substitution with a suitable halogenating agent such as Bγ2, Cl2, I2, IC1 or SO2CI2. This reaction can be carried out using a compound or base of compound IX in a suitable solvent such as acetic acid, HC1 / ethanol or water, with or without a suitable base, such as an alkali metal acetate such as sodium acetate. Performed at temperature. This paper size applies to China National Standard (CNS) A4 (210X 297 mm) (Please read the precautions on the back before filling this page)

A7 B7

N- (Bn) 2 Printed by the Consumers' Cooperative of the Central Standards Bureau of Didi Ministry 568786 V. Description of Invention

㈣ (XIII) (VU1) is converted from a compound of formula XΠ into a compound of formula XIII, wherein Ri is a hydrogen C1-C6 group or a C3-c6 cyclofluorenyl group and R2 is a carbamoyl group, which is used in a suitable anhydrous solvent such as tetrahydrofuran or diethyl ether. Suitable alkyl-lithium or metal 'for example: butyl lithium, lithium or magnesium swarf for metal, element exchange reaction' and then bury it with a suitable alkyl compound such as methyl iodide, ethyl bromide or propyl And the reaction temperature is in the range of _78 to room temperature, and then use a suitable catalyst containing palladium, rhodium, platinum or nickel in a suitable solvent, such as: acetic acid or ethanol, the reaction temperature of A +20 C to +120 c Hydrogenation reaction may be carried out, or be treated with other electrophilic agents such as acetaldehyde or methyl formate, and the benzyl group may be cleaved, followed by appropriate operations. The reaction is available at. c. Reaction temperature to room temperature. If acetaldehyde is used as an electrophile, following the above-mentioned reaction, use a suitable catalyst containing barium, germanium, platinum, or nickel in a solvent such as acetic acid or ethanol at +20 ° C. Up to +120 X: into the cup at the reaction temperature-^ 丄 lamp oxidation reaction, make benzyl S-21-this paper size applies Chinese National Standard (CNS) A4 specification (210X 297 mm) (Please read the note on the back first (Fill in this page again)

568786 A7 -------—__ __B7 V. Description of the invention (19) Reduction and cleavage of benzyl. If using methyl chloroformate as the electrophile, following the above reaction, use methyl ester in a suitable solvent such as diethyl ether or tetrahydrofuran and use a suitable reducing agent such as lithium aluminum hydride at + 20 ° C to reflux. The reduction reaction is performed at the reaction temperature, and then a suitable catalyst containing palladium, germanium, platinum or nickel is used from benzyl alcohol in a suitable solvent such as acetic acid or ethanol at +20. At a reaction temperature of 0 to +120, a hydrogenation reduction is performed, and the nodular group is cleaved. When R! Is hydrogen, before the lithiation step, protect the hexahydropyridine 4 nitrogen with a suitable protecting group such as: fluorenyl 'or another protecting group known to experts in the related art, and then eliminate it using methods known in the related art. Protecting the group results in a compound of formula XIII. (b〇 from the compound of formula xm, where R] is hydrogen and converted to the compound of formula χιν (please read the precautions on the back before filling this page)

, 1T

R

NH N I Ri

Member of the Central Standards Bureau of the Ministry of Economic Affairs J: Consumer Cooperatives

N! R (XIII) (Xiv) where Rc is a suitable protecting group 'It is in a suitable solvent such as or in aerosol' Use a suitable protecting reagent, such as: dicarbon dichloromethane third butyl ester This paper is applicable to China Standard (CNS) A4 specification 22

NH 2 568786 A7 B7 V. Description of the invention (20) and appropriate bases such as: triethylamine or K2CO3, protected at a temperature of -20 ° C to + 60 ° C; hexahydro said to cultivate the ring. (Please read the notes on the back before filling out this page) (X) From compounds of formula IX, where Ri is hydrogen, Ci-Cs alkyl or CVC6 cycloalkyl, converted into compounds of formula xv, where Ri is hydrogen, Ci-C6: Ci or C3-C6 cycloalkyl, which uses a suitable catalyst containing palladium, rhodium, platinum or nickel, in a suitable solvent such as acetic acid or ethanol, at +20 ° C to +120 ° C Hydrogenation is carried out at the reaction temperature to cleave the benzyl group. (xi) The compound of formula IX, where Ri is hydrogen, is converted into the compound of formula XVI.

γ ^^^ N- (Βη) 2

I R. (IX) -23-

N- (Bn) 2

(IX) (XV) This paper size applies to Chinese National Standard (CNS) A4 specification (210X 297 mm) 568786 A7 B7

NH. (XV) Printed by the Consumer Standards Cooperative of the Central Bureau of Standards of Didi Ministry. 5. Description of the invention (21 where Rc represents a suitable protecting group, which is a) Use a catalyst containing palladium, germanium, platinum or nickel in a suitable solvent For example: gasification in acetic acid or ethanol at a reaction temperature of +20 ° C to +120 ° C, or b) in a suitable solvent such as methanol in the presence of ammonium formate and P (j / c Remove the hydrazone at a reaction temperature between +20 ° C and reflux. Following this reaction, 'in a suitable solvent such as dichloromethane or chloroform, use a suitable protective agent such as di-third butyl dicarbonate Protect the hexahydropyridine ring with a suitable base such as: diethylamine or K2 C03 at a reaction temperature of -20 ° C to + 60 ° C. (Xii) From the compound of formula XV, where & is hydrogen, CVC6 alkane Or C3-C6 cycloalkyl, amidated to form a compound of formula XVII

Hal

NH, «1 (XVII) This is an aromatic electrophilic substitution reaction using a suitable halogenating agent such as: Br2, Cl2, I2 s IC1 or SO2CI2. The reaction can use the salt or base of compound XV in an appropriate solvent such as: acetic acid, HC1 / ethanol or water, with or without 24 paper standards applicable to China National Standard (CNS) A4 (210X 297 mm) (Please read first (Notes on the back then fill out this page)

568786 A7 B7 V. Description of the invention (22 Use a suitable base, for example: alkali metal acetates such as: sodium acetate, at room temperature of -20 U; reaction temperature. (Xiii) from the compound of formula XVII, R ^ j wTTT. The substance T is hydrogen and converted into a compound of formula XVIII

Hal

NK

'N i R (Please read the notes on the back before filling out this page) I Ri (XVII) (XVIII) Printed by Dibu Central Consumer Corporation where Rc is a suitable protecting group, which is in a suitable solvent such as : Digas methane or chloroform, use appropriate protective reagents, such as: di · third butyl dicarbonate, use appropriate bases, such as: triethylamine or K2C03, at a reaction temperature of _20 t to +60, protect Hexahydro-plowing ring. (XIV) by the compound of formula XIX, wherein R2 is a CVC6 alkoxy group (when X is 0, described in S-0, Thorberg et al., Acta Pharm. Suec. 1987 24, 169-182; When X is CH2, it can be obtained from a commercial product), which is a racemate or an enantiomer, and is halogenated to obtain a compound of formula XX. -25- This paper size is applicable to China National Standard Engine (CNS) A4 specification (210X297) Centimeters)

NHn (XX) Member of the Central Standards Bureau of Didi Ministry, printed by τ Consumer Cooperative Μ B7 V. Description of Invention (23

(XIX) It is an aromatic electrophilic substitution reaction using a suitable hydrating agent such as ΒΓ2, Cl2, 12, 2, IC1 or SO2CI2. The reaction can be performed using a salt or test compound XIX in a suitable solvent such as acetic acid, HC1 / ethanol or water, with or without a suitable test such as a metal acetate such as: sodium acetate 'and at -20 ° C to the chamber. The reaction was carried out at a warm reaction temperature.

N- (Bn), (XXI) (XV) benzylated from a compound of formula XX (racemate or enantiomer) to obtain a compound of formula XXI, which is compatible with a suitable amidating agent such as: amidino bromide Or fluorene-based gas, or activated alcohols such as: benzyl mesylate or sulfonyl tosylate. The reaction can use a salt or base of formula XX in a suitable solvent such as: N, N-dimethylformamide, acetone or acetonitrile, with or without a suitable base such as: triethyl 26- This paper is applicable to Chinese countries Standard (CNS) A4 specification (210X 297 mm) (Please read the precautions on the back before filling this page)

568786 A7 B7 5. Description of the invention (24) Amine, NaOH, NaHC03, per K λ. Wide; K2CO3, in the temperature range of +20 C to + 150 ° C. Contains high-quality catalysts such as alkali metal teeth such as potassium iodide or steel iodide to speed up the reaction. .

N- (Bn),

N- (Bn), Ri: (XXI) (XXII) (xvi) is converted from a compound of formula XXI into a compound of formula χχιι, its central hydrogen, Ci-C6 alkyl or CrC6 cycloalkyl and 1 is Ci_c6 alkoxy, which It is reacted with a compound of formula XXIII, wherein Ri is hydrogen, Ci_c6 alkyl, or cycloalkyl. Η—Ν The Consumer Cooperative of the Central Bureau of Standards

NIR (XXIII) This method can be used in a suitable solvent, such as aprotic solvents such as: benzene, toluene, dioxolane, tetrahydrofuran, or Ν, Νdimethylformamide, using 27- this paper size applies China National Standard (CNS) A4 specification (210 × 297 mm) 568786 A7 ~ ___ _ V. Description of the invention (25) — ~ Suitable bases such as: sodium tert-butoxide or bis (trimethylsilyl) charged lithium amide, in Suitable palladium catalysts such as: PdZ2, L'2Pd (〇) or L, 2PdZ2i, where ζ represents halogen, such as: chlorine or bromine, and ^ represents suitable ligands, such as: triphenylpentene, tri-o-toluene "Phosphine, trifurylphosphine, triphenylmethane, or dibenzylideneacetone 'with or without the addition of ligand L", such as: triphenylphosphine, tri-o-pyranylphosphine, trifurylphosphine, triphenyl Fluorene or dibenzylideneacetone with or without the addition of ligand L "such as: triphenylphosphine, tri-o-tolylphosphine, trifurylphosphine, 2,2, _bis (diphenylphosphine difluorene) (As a racemate or an enantiomer) or triphenylphosphonium and is carried out at a reaction temperature of +20 ° C to +150 ° C. (Xvii) Conversion of a compound of formula XXII to 4 XXIV Compound

A

I

Ri (XXIV) where Ri is hydrogen, Ci-C6 alkyl or CrC6 cycloalkyl and R2 is Ci_C6 ^ oxygen, which uses a catalyst containing palladium, germanium, platinum or nickel in a suitable solvent such as acetic acid or ethanol The reaction is carried out at a reaction temperature of +20 ° C to +120 ° C. (xviii) From the compound of formula XXIV, where R! is hydrogen, which is converted into XXV -28- This paper size applies Chinese National Standard (CNS) A4 specification (210X 297 mm) (Please read the notes on the back before filling (This page)

Printed by the Consumer Standards Cooperative of the Central Standards Bureau of Didi Ministry 568786 A7 B7 V. Description of Invention (26)

(XK1V) (XXV) (Please read the precautions on the back #Fill this page first) Printed by the Consumer Standards Cooperative of the Central Bureau of Standards, where Rc is a suitable protecting group, which is in a suitable solvent, such as: methylene Or chloroform, use a suitable protective agent, such as di-tertiary butyl dicarbonate and a suitable base, such as triethylamine or K2C03, to protect hexahydropyridine at a reaction temperature of -20 ° C to +60 ° C Ploughing the ring.

NH

O ^ OH

N,

-29- This paper size is in accordance with Chinese National Standard (CNS) A4 (210X 297mm) 568786 A7 B7 V. Description of the invention (27 (xix) by compound of formula XV, where R1 is Cl-C6 alkyl or C3-C6 Cycloalkyl 'is converted into a XXVI compound, where γ is NHCO and R3 is as defined in the general formula Ϊ above, which is related to the appropriate formula XXVII benzoic acid (in the form of a fluorene-based gas activation type) in a suitable solvent such as: methane or In chloroform, use a suitable base, such as trialkylamine, such as triethylamine, for the halogenation reaction, or use benzoic acid of the formula χχνπ with an activating reagent, such as: N, N, -carbonyldiimidazole, N, N , -J-hexylcarbide-carbodiimide or an epi-epoxybenzyl chloride, using a suitable test such as: N-methylmorpholine, in a suitable solvent such as: N, N-dimethylformamide or tetrahydrofuran The reaction is tritiated, and the reaction temperature can be + 20 ° C to + 150 ° C. 2. If Y is CONH and X is CH2 or 0. (1) From the compound of the formula XXVIII, where the 2 is Cl_C6 alkane Oxygenation (as a racemate or enantiomer) nitrates to give compounds of formula χχΐχ

R

OR. Printed by a member of the Central Standards Bureau of the Ministry of Economic Affairs, Consumer Cooperative (XXIX) (XXIX). Its center is C ^ -C: 6 alkyl, which can use suitable nitrating agents such as nitric acid or nitric acid and sulfuric acid in suitable solvents such as: Aromatic electrophilic substitution reactions are performed at a reaction temperature of -20 c to room temperature in acetic acid, acetic anhydride, or water. (ii) Hydrolyzed by a compound of formula XXIX 'It is under acidic conditions, using acid -30-This paper size is applicable to China Standard (CNS) A4 size (2K) x 7 ^ J · (Please read the note on the back :: AA (Matter 4 fill out this page)

568786 Bu Yi A7 --------------- B7 V. Description of the Invention (28) The Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs of the People's Republic of China, such as H2S〇4 HC1, HBr In a solvent such as, ethanol, methanol; acetic acid or a compound thereof, the reaction is performed between +2 ()) and the reflux reaction temperature, or under a base, using a base such as NaOH Or κ〇η, in a compound such as Η 〇 20, ethanol, methanol or a mixture thereof, and the reaction temperature from 1 to reflux to produce a compound of formula χχχχ.

(XXXI) (iii) Conversion from a compound of formula XXX, wherein Chi 2 is Cl-C6 alkoxy, to a compound of formula XXXI, where Y is CONH and R 2 or Ci-Cs cycloalkyl, using a suitable base such as: Alkylamines, such as: triethylamine, or use of activators such as: N, N'-carbonyldiimidazole, n, N-dicyclohexylcarbodiimide, diphenylphosphine chloride '. Use appropriate examples: N- Methylmorphine, in a suitable solvent such as: dichloromethane, aerobic, toluene, N, N-dimethylformamide, dioxolane or tetrahydrofuran, activate the acid functional group of the compound of formula XXX to form a fluorenyl group The halide is then added with the appropriate aniline XXXII, where R3 is as defined for formula I above. The reaction temperature is between 0 ° C and + 120 ° C. -31-This paper size is in accordance with Chinese National Standard (CNS) Α4 specification (2lOX 297 mm) (Please read the precautions on the back first, then fill out this page)

568786 A7 B7 Printed by the Consumer Cooperative of the Central Bureau of Standards of Didi Ministry. 5. Description of the invention (29) (iv) The compound of formula XXXI is converted into the compound of formula XXXIII, where γ is COlSfH and R3 is as defined by general formula

(XXXIII)

It uses a catalyst containing palladium, germanium, platinum, or nickel in a suitable solvent such as ethanol, methanol, or ethanol at a reaction temperature of +20 ° C to +120 ° C, or with Sodium sulfite is reduced in a suitable solvent. / 3. Convert a compound of formula XXXIV to form a compound of formula XXXV

> Factory > ° J one or two V〇 = y \ — ^ 0J ho y / XXXIV XXXV The preparation method is a) The nitrile of the compound of formula XXXIV in a suitable solvent such as: methanol aqueous solution or ethanol aqueous solution. In the presence of NaOH or K0H, it is hydrolyzed at a reaction temperature between room temperature and reflux, and then b) the amidine and ketal formed from the above under acidic conditions in a suitable solvent such as: In the presence of an acid such as H C1 or HBr, it is hydrolyzed at a reaction temperature between room temperature and reflux. 32 (Please read the back first; '4 Italian matters before filling out this page)

This paper size applies the Chinese National Standard (CNS) A4 specification (210X 297 mm) 568786 V. Description of the invention (30. Preparation of the final product, ..., ... / ..., the present invention; another purpose is to prepare the general formula 1 Compound 10,000 / 1, A (ii), B or C, which is Am gandou, r »r y'y 'Y is NHCO and X if 1 is CVC6 or C3-C6, R2 and R3 such as When the above formula 1 is defined, the formula A

Y

(Please read the 4 notes on the back first and fill in this page)

, * 5 mouth Ding

NIR

NIR ㈧ 6

Printed by the Consumer Cooperative of the Central Standards Bureau of Didi Ministry for dehydration with activated benzoic acid of formula XXVII, or acidification with benzoic acid of formula XXVII and activator. Therefore, according to the tritiation method of method A (i), an activated form XXVII of fluorenyl chloride may be used as appropriate benzoic acid, wherein R3 is as defined in the general formula I above, and in a suitable solvent such as digas methane or aerosol, a suitable base is used. For example: Trialkylamine such as diethylamine, at -20 C to reflux temperature, or use the formula XXvii -33-

568786 A7 B7 V. Description of the invention (31 Benzoic acid, where R3 is as defined by the formula I above, and activator carbonyldiimidazole, N, N'_dicyclohexylcarbodiimide formula 'For example: Use the appropriate test: N- Methyl morphine, in a suitable solvent such as: benzylphosphinomethoxamine or tetrahydrofuran, at +20 ° c to + Γ50 ec. Mix When Ri hydrogen, Y is NHCO, Rc is a protecting group and χ When Rs is as defined in the above general formula I, it is tritiated by the compound of formula B. Please read the back of the gas test first.

Printed by the Consumer Standards Cooperative of the Central Bureau of Standards (B) (I) Therefore, according to the sewing method of method A (ιι), an appropriate benzoic acid of the formula χχνπ in the form of fluorenyl chloride activation can be used, in which R3 is as shown in the above formula. Define, in a suitable solvent such as: dichloromethane or chloroform, and a suitable base such as · trialkylamine such as: diethylamine, perform a chemical reaction between -20 C and reflux temperature, or use the formula -34- Standards are applicable to Chinese National Standard (CNS) A4 specifications (210X 297 mm) 568786 A7 B7 V. Description of the invention (32) XXVii benzoic acid, where R3 is as the meaning of the formula I above and 'activator' For example: n, n,- Carbonyl diimidazole, N, N, dicyclohexylcarbodiimide diphenylphosphine chloride, use a suitable base such as: N-methylmorpholine, and a suitable solvent such as: N, N-dimethylformamide Or in tetrahydroan, at a reaction temperature of + 20 ° C to + 150 ° C, and then in a common agent such as " dichloromethane or chloroform, using a suitable acid such as: trifluoroacetic acid, in + Hydrolysis at a reaction temperature between 20 ° C and +60 ° C, removing the protective group Rc °

B If Y is CONH, X, Ri, R2 and Hua 3 are as defined in the general formula I above (Please read the precautions on the back before filling this page)

Order

Printed by a member of the Central Bureau of Standards. X Consumer Cooperatives (c), (i) reacts with a compound of formula XI in which L is an ionic group. Therefore, the reaction according to method B can be combined with the compound of formula XI ^^ #

% Order, where R -35- this paper rule ^ applies to China National Standard (CNS) A4 specifications (21〇1 < 297 mm1 " " ~ ____ 568786 A7 —— 一 ——-_— 一 ——_ B7 V. Description of the invention (33) ~ As defined in the general formula I above and L is a leaving group, for example: halogen, such as: gas or bromine 'or sulfonium- or arylsulfonyloxy group, such as: p-toluenesulfonyloxy group, the The reaction can be performed in a suitable solvent such as ethanol, butanol, N, N-dimethylamidamine, acetonitrile, or a mixture of water and acetonitrile, with or without a suitable base such as K2C03, NaHCCb or KOH, at +20. : And the reaction temperature of 150 ° C. C If Y is NHCO, R2 is from and X, Ri, and R3 are as defined in the above general formula I, the compound of formula D is consumed by the staff of the Central Standards Bureau of Drip Department. Printed by a cooperative

Y

NIR

N-R (D) (I) H suitable halogenating agent such as: Br2, Cl2, I2, IC1 or S02C12 reaction. Therefore, according to the reaction of Method C, an aromatic electrophilic substitution reaction can be performed using a halogenating agent such as: Br2, Cl2, I2, IC1, or SOAl2. The reaction can be carried out using the salt or compound of compound D in a suitable solvent such as acetic acid, HC1 / ethanol or water, with or without a suitable base, such as a metal acetate such as: ethyl-36- paper rule 1¾ Ι 1 Π Ι3Π J also / \ (Please read the > i notice on the back before filling in this page)

A 5 JN J Thousand I h i i-

S Gong 7 2y X 568786 Α7 B7 V. Description of the invention Sodium (34) is carried out at a reaction temperature between -20 C and room temperature. Operation method 1 5-Η T1 r anti-antigen-intermediates and starting materials production method 1 (R) -2-N, N-diamidoamino_8_methoxy_ ;; 2,3 , 4_tetrahydrofan added potassium carbonate (53 g, 0.39 mol), potassium iodide (catalyst amount), and succinyl bromide (34 ml, 0.28 mol) to (R) _8_methoxy_2 Amine_1 2 3 4_ tetrahydrofluorene hydrochloride (24 g, 0.6 M mole) in acetonitrile (600 ml). The reaction mixture was stirred at reflux for 35 hours. After the precipitate was filtered off, the acetonitrile was emptied and the residue was distributed between diethyl ether and water. The organic product 7 was dehydrated (NS〇4) and the crude product produced by total evaporation was passed through a Shixi gel column using hexane / ethyl acetate Vinegar (3: 1) was purified as the eluent. Yield:% g (91%) of the title compound as a white solid .. mp 105-1107. (:; [A] 21D + l24. (Ci 〇, aerobic); EIMS (70 eV) m / z (relative strength) 357 (100, M +) Method 2 (11) -7-Team > '1-Dibenzylamino-5,6,7,8-tetrahydro_1_ 荇 Fin Manchu Central Standards Bureau Offset Consumer Cooperative Co., Ltd. (Please read the precautions on the back before filling this page)

(R) -2-N, N-A + amino-8-methoxy-1,2,3,4-tetrahydrofan (43 g 0.12 mole) was dissolved in ether (800 ml), dropwise An excess of HC1 ether solution precipitate was added and filtered to dry out, resulting in a white solid. This crude product (42 g 0.11 mol) was dissolved in anhydrous dichloromethane (丨 liter) and cooled to -6 (rc. Tribromide dissolved in anhydrous dichloromethane (00 ml) was added dropwise to the solution. Boron (J 6 ml '0. 15 mol). The reaction temperature was raised to -5 and kept overnight, and a 2 M aqueous ammonium hydroxide solution was added dropwise to this ice-cold solution. The mixture was extracted twice with dichloromethane. Organic phase dehydration (Na2s〇4), filtration and emptying to dissolve 37 paper ruler_M specifications (210X297 mm) Printed by the Central Bureau of Consumers Cooperative of the Ministry of Labor 568786 A7 ____________ B7 V. Description of the invention (35) — ~~ One dose produces crude residue. After silica chromatography (eluent: digas methane), 34 g (yield 93%) of the title compound is a viscous transparent oil: [a] 2lD + u8〇 ( c 1.5, gas imitation); EIMS (70 eV) m / z (relative strength) 343 (53, M +) 〇 Production method 3 (R) -2- (7-N, N-diamidoamino_5,6, 7,8-tetrahydro_1_phenoxy) -2_methylpropanilamine takes (R) -2_N, N-diamidoamino_5,6,7,8-tetrahydro_1_pyrophenol (10 g, 29 mmol) in sodium hydride (80% oil, 0.96 g, 32 Mol) in anhydrous monooxan (150 liters) and stir for 1 hour. Add 2-bromo_2_methylpropanamide (4.8 g, 29 mmol), as described in He Goz (c. utts); MR Sonthcott, J. Chem, Soc. Perkin Trans,! 199, 767-770), and the reaction mixture was heated at loo ° C for 2.5 hours. After cooling down, the precipitated > Sodium odorant 'was emptied to evaporate the sap, and the residue was distributed between water and dimethyl ether. The organic phase was separated, dehydrated (NkSO4), filtered and evaporated. The resulting crude product was purified on a silica gel column using dichloromethane as the eluent. Yield: 9.6 g (76%) of the title compound as white crystals: 11 ^ 125-126. (^; [a] 21D + 98 ° (c 1.1, aerodynamic); EIMS (70eV) m / z (relative strength) 428 (13, M +). Method 4 (R) -N- (7-N, N_dibenzylamino-5,6,7,8 · tetrahydro-l-fluorenyl) -2-hydroxy_2-methylpropanamide with sodium hydride (80% oil, 1.4 g, 47 mmol) (Ear) to (r) _2_ (7-N, N-diamidoamino_5,6,7,8-tetrahydro-stuboxy) _2_methylpropanamine 38 This paper is for Chinese country Standard (CNS) A4 specification (210X297 mm) (Please read the precautions on the back before filling this page), 11

568786 A7 B7 V. Description of the invention (36) (9.1 g, 21 mmol) anhydrous 1,3-dimethyl_3,4,5,6-tetrahydro-2 (1 ^ 1) -pyrimidinone: (10 ml) and an anhydrous Ν, Ν-dimethylformamide (100 ml) solution, the reaction was heated at 130 ° C for 8 hours. The solution was poured into a mixture of ice and water and extracted three times with ethyl acetate. The combined organic phases were dehydrated (Na2S04), filtered and evaporated in vacuo. Chromatography with silica (eluent: chloroform / ethanol saturated with NH3, · 100 · · 0.5) yields 7.6 g (84% yield) of white crystals: mp 134-135 ° C; [a] 21D + 130 ° (c 1.1, chloroform), · EIMS (70 eV) m / z (relative strength) 428 (1, M +). Production method 5 (feet) -2_1 ^,] ^-Di-amino-8-amino-1,2,3,4-Tetrachlorotrial Trial Department Central Standards Bureau Shellfish Consumer Cooperative Co., Ltd. (Please read the back first Note for refilling this page) Take (R) -N- (7-N, N-dibenzylamino_5,6,7,8tetrahydro-1_fluorenyl) -2-hydroxy-2-form Propylamine (7.4 g, 17 mmol) was dissolved in a mixture of ethanol (200 ml) and 20% aqueous HC1 solution (300 ml) and heated to reflux for 8 hours. The ethanol was evaporated in vacuo and the remaining solution was washed twice with diethyl ether and cooled on an ice bath. After alkalizing with a 45% aqueous sodium hydroxide solution, the mixture was extracted with dioxane. The combined organic phases were dehydrated (Na2S04), filtered and evaporated in vacuo. Purification on a silica gel column using eluent as eluent yielded 3.8 g (76% yield) of the title compound as a light brown oil: [a] 21D + 124. (C 0.9, chloroform); EIMS (70 eV) m / z (relative intensity) 342 (92, M +). Production method 6 (11) -1_ (7-fluorene small diamine amino group_5,6,7,8_tetrahydro-1-fluorenyl group) _4_ > ^ methyl hexahydropyridine-2,6-dione addition 1, Γ-carbonyldiimidazole (6.0 g, 37 mmol) to anhydrous tetrahydrofuran (250 ml) containing methyliminodiacetic acid (2.7 g, 18 mmol) ___ -39- ^^ 张Standards are applicable to China ~ 5 ^^ 'quasi (CNS) M specifications (2 丨 0 > < 297 Gongchu) Ministry of Central Standards Bureau and Consumer Cooperatives India 568786 A7 B7 V. Description of the invention (37) ~ Mixing suspension in. The reaction mixture was heated at reflux for 1.5 hours. N-diamidine; amido-1,2,3,4-tetrahydropyrene (5.7 g, 17 mmol) was added and stirring was continued for 17 hours under reflux. Add another portion of 1,1, carbonyldiimidazole (2.9g, 18 mmol, and continue heating at reflux for 17 hours. The solvent was evaporated and the crude product was passed through a silica gel column using NH3 saturated chloroform / ethanol (100: 0 5) Purification by eluent. Yield of 6.6 g (87%) of the title compound: [a] 21D + 90o (c () 52, aerosol); EIMS (70 eV) m / z (relative strength) 453 ( 8, M +). Production method 7 (R) _2_N, N-Dimethylamino-8 · (4-methylhexahydro p ratio p well group) ", 2,3 4 -tetrahydrophosphonium addition (11)- 1- (7-Team dibenzylamino_5,6,7,8-tetrahydro-1-fluorenyl) _4-methylhexahydropyridine-2,6-dione (1.4 g, 3.1 mmol Ear) to an aqueous acetic acid (70 ml) suspension containing lithium hydride (0.57 g '15¾ mol). The anti-corrosion mixture was heated at reflux for 7 hours. Water (0 60 ml) was added sequentially, 15% sodium hydroxide Aqueous solution (0.6 ml) and water (1.8 ml) were used to stop the reaction. The mixture was purged, dehydrated (Na: 2SO4), and evaporated in vacuo. The silica gel column was dissolved in NH3 saturated gas / ethanol (100: 2) to dissolve. The solution was purified to yield 10 g (79% yield) of the title compound as a viscous oil: [a] 2iD + 53〇 (c 0 5, gas imitation); EIMS (70 eV) m / z (relative intensity) 425 (2, M +). Preparation method 8 (magic-5- / odor-2 _! ^,! ^-A: ^ amino group -8- (4-fluorenylhexahydro? Than _-; [_group) -1,2,3,4 · tetrahydrophosphonium Add all the bromine (370 μl, 72 mmol) to (r ) _2_n, n_ Dimethylamino-8_ (4-methylhexahydropyridine-butyl) -1,2,3,4-tetrahydropyrene (28 g (please read the precautions on the back before filling this page) )

-40- 568786 A7 printed by the Central Standards Bureau of Didi Ministry _τ Consumer Cooperative Co., Ltd. A7 _____ ___B7 V. Description of the invention (38) " '6.5¾ Moore' and sodium acetate (6.8 g, 83 mmol) acetic acid (1 〇mL) solution, the reaction was stirred for 5 minutes. The solvent was evaporated and the remaining solids were distributed between water and methylene chloride and cooled on an ice bath. The aqueous phase was basified with 2 μ aqueous sodium hydroxide solution and the phases were separated. The organic phase was dehydrated (Na2S04), filtered, and evaporated in vacuo. The resulting crude product was purified on a silica gel column using NH3 saturated chloroform / acetic acid (100: 2) as the eluent. Yield: 2 g (61%) of viscous brown oil. EIMS (70 eV) m / z (relative strength) 503 and 505 (0.6, Μ +). Production method 9 (R) -2-N, N · dibenzylamino_8- (hexahydropyridine_1_yl) _ι, 2,3,4_tetrahydropyrene (R) _2-N, N_ Monoammonium-8-amino-1,2,3,4-tetrahydrodiamine (9.8 g, 39 mmol) and bis- (2-aminoethyl) amine hydrochloride (55 g, 32 Mmol) was dissolved in n-butanol (80 ml). The reaction mixture was stirred at 100 t. After 65 hours, the mixture was filtered, and the solvent was evaporated in vacuo. Purified via a silica gel column using chloroform / methanol / concentrated ammonium hydroxide (95: 5: 0.5) as the eluent to produce 6.0 g (yield: 51%) of the title compound as a viscous oil: [a] 2iD + 72 〇 (c 丨 〇, gas imitation); EIMS (70 eV) m / z (relative intensity) 41 1 (2, M +). Production method 10 (R) _2 · Amine_8- (hexahydropyrine-1-yl) _1,2,3,4_tetrahydropyrene Add ammonium formate (20 g, 0.32 mol) and palladium 10% / Activated carbon (1.9 g) to (R) _2-N, N-mono + amino-8- (hexahydropyridine-1 · yl) -1,2,3,4_tetrahydroqin (5.5 G'1 :) zemol) in methanol (400 ml) solution. The mixture was refluxed for 1 hour and the palladium was filtered off. The solvent was evaporated and the residue was distributed between dichloromethane and 2M ammonium hydroxide solution. Separate the organic phase, dehydrate (Na2s〇4), evaporate it through air, and evaporate it. The resulting crude product is passed through a silica gel column using chloroform / ethanol ^ 's Zhang scale. Applicable to China National Standard (CNS) A4 regulations; ------- (Please read the notes on the back before filling this page)

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568786 V. Description of the invention (39; Ethyl chloride oxidation money (80: 20: 2.5) is purified by eluent. Yield ·· 24g (Please read the notes on the back before filling this page) (76 / 〇 ) 'Chemical oil: 21] + 99. ^ 10, chloroform); 僵 8 (70 eV) m / z (relative strength) 23 1 (24, m +). ^ Production method 11 (outer 2 · amino group ^ bromo-8- (hexahydropyridine-l-yl) -1,2,3,4-tetrahydrofluorene according to the general method of production method 8, by (R) _2 _Amino_8_ (hexahydropyridyl) 1,2,3,4-tetrahydronaphthalene to prepare the title compound. Dichloromethane / ethanol / concentrated ammonium chloride (80: I 2) was used as a silica gel column to obtain The eluate was purified to yield g (67% yield) of light yellow brown viscous oil: [a] 2lD_6 2. ⑻i, chloroform; EIMS (70 eV) m / z (relative strength) 309 and 311 (3 5 , M +). Preparation method 12 (Magazine 4- (7-amino-4-bromo-5,6,7,8_tetrahydroberberyl) hexahydropyridine small carboxylic acid third butyl ester is consumed by employees of the Central Standards Bureau of Drip Ministry Cooperative printed to add di-tertiary butyl dicarbonate (056 g, 2.6 mmol) in methane (10 liters) to ice-cold content (R > into amino-5-bromo-8_ ( Hexahydropyridine-Bulkyl) One of 1,2,3,4-tetrahydropyrene (0.8 g, 26 mmol) and triethylamine (0 53 ml '3.9 μmol) (50 ml) of the solution. After the addition, the reaction was stirred at ambient temperature for 1 hour. Water (00 ml) was added, and the mixture was cooled on an ice bath. The aqueous phase was basified with 2M sodium hydroxide aqueous solution, and Phase. The organic phase was dehydrated (NajO4), filtered and evaporated in vacuo. The resulting crude product was purified by a silica gel column using chloroform / methanol / concentrated oxidation residue (9 5: 5: 0.5) as the eluent. Yield: 0.41 g (38 %) Viscous colorless oil: [a] 2iD + 13〇 (c = i, aeroform); EIMS (70 eV) m / z (relative strength) 409 and 411 (75, M +). -42- 本Paper size applies Chinese National Standard (CNS) A4 (21 〇χ 297mm) 568786 Α7 Β7 Member of the Central Bureau of Standards of the Ministry of Economic Affairs_τ-Consumer Cooperatives Yin Fan V. Description of the Invention (40) Method 13 (R) -N- [5-Bromo-8- (4-Third-butoxycarbonylhexahydropyracine-1- ), Ι, 2,3,4-tetrahydro-2-¾: yl] -4_morpholine benzidine and 4-morpholine benzoic acid (0.50 g, 2.4 mmol, illustrated by J. Digg Degutis; L. Rasteikiene; A. Degutiene, Zh, Org, Khim, 1978, 14 (10), 2060-2064) Soluble in thionyl chloride (10 ml ). After 2 minutes, thionyl chloride was evaporated in vacuo, the residue was treated with toluene, and the solvent was evaporated again. Crude tritium base gas (81 mg, 0.36 mmol) was dissolved in dichloromethane (10 ml). , Added dropwise to (R) _4_ (7_amino-4_bromo-5,6,7,8_tetrahydro-1_fluorenyl) hexahydro p ratio p well-i_renylic acid tert-butyl diamine ( 140 mg, 0.34 mmol) and triethylamine (71 μl, 0.51 mmol) in a solution of methane (10 ml). After the addition, the reaction was stirred at ambient temperature for 15 minutes, and then Wash with dilute aqueous sodium bicarbonate solution and separate the phases. The organic phase is dehydrated (NaSSCU), filtered and evaporated in vacuo, and the residue is passed through a silica gel column. Purified with NH3 saturated chloroform / ethanol (100: 2) as the eluent. Yield: "0 Aike (79%) dry mesh colorless oil: [a] 21D-ll. (C == l, aerosol ); TSPMS m / z (relative intensity) 599 and 601 (35, M + +1). Preparation method 14 (R) -2-Amino-8_ (4-methylhexahydropyrine-1-yl) -i, 2,3,4-tetrahydrogen, and ammonium formate (14 g, 56 mmol) And free (10%) / activated carbon (4 g) to (R) -2_N, N-monofluorenylamino-8- (4-methylhexahydro p ratio p well _ι_yl) _ 1 , 2,3,4-Tetrahydropyrene (4.0 g, 9.4 mmol) in methanol (250 ml). The mixture was refluxed for 3 hours and the palladium was filtered off. The solvent was evaporated in a vacuum, and the residue was distributed between dimethyl formamide and a 2M ammonium hydroxide solution. Separate the organic phase and remove -43-

(Please read the notes on the back before filling this page)

Order

568786 A7 B7 V. Description of the invention (41 (Please read the notes on the back ¾ before filling out this page) Water (NaaSO4), filtration, and vacuum evaporation, the crude product produced is passed through a silica gel column using chloroform / methanol / concentrated hydrogen Ammonium oxide (90: 9: 0 5) was purified by eluent. Yield: I · 9 g (83%) of oil: [a] 2iD_2.7. (Ci 〇, aerosol); EIMS (70 eV) m / z (relative strength) 245 (5, M +). Production method 15 (R) _2-amino · 5-bromo · 8_ (4-methylhexahydropyridine_1_jibu ^ rentetrahydropyridine method The general method of 8 is to prepare the title compound from (R) _2_amino_8gas 4_methylhexahydropyridine • 1-yl) -1,2,3,4-tetrahydrofluorene on a silica gel column. Purified using aerosol / ethanol / concentrated ammonium hydroxide (80: 20: 2) as eluent to produce 63.0 mg (yield 89%) of a viscous colorless oil · EIMS (70 eV) m / z (relative strength) 323 and 325 (20, M +). Preparation method 16 (&) _ 2-Amino-8-bromo-5-fluorenyloxy-1,2,3,4-tetrahydrofluorene hydrochloride Central Standard Bureau Employee Consumer Cooperative Co., Ltd. was exposed to nitrogen atmosphere, and (R) -2-amino-5 · methoxy · 1,2,3,4-tetrahydrophosphonium hydrochloride (5.0 g, 23 mmol) was dissolved. to In acetic acid (300 ml). After adding sodium acetate (5.5 g, 70 mmol), add the entire amount of bromine (3.5 g, 23 mmol) in one portion. The mixture was stirred at room temperature for 5 minutes. The solvent was removed by emptying and produced. The residue was distributed between ethyl acetate and NaOH (2M). The layers were separated and the aqueous phase was extracted twice with ethyl acetate. The organic layers were combined and dehydrated (Na2S04). The solvent was removed by emptying, resulting in a brown oily residue. HC1 in ethanol (3 M) was added to precipitate the HC1 salt from ether / dichloromethane: Yield: 7.7 g (94%). Recrystallized from methanol to give needle-like crystals of the title compound: 264- 265 ° C; [oc] 21D + 54. (cl, MeOH); EIMS (70 eV) m / z (relative strength) 257 (30, M +, 81Br), 255 (3 1, M +, 79Br). -44 · This paper size applies to Chinese National Standard (CNS) A4 (210X 297 mm) 568786 M Manchuria National Standards Bureau Negative Two Consumer Cooperatives Co., Ltd. Imprint 5. Invention Description (42M Law 17 (R) -8-Bromo- 2-N, N_dibenzylamino · 5-methoxy-1,2,3,4_tetrahydrodistillation of (r) -2-amino-8-bromomethoxy-m4 · tetrahydrofluorene Hydrochloride (45 g '17.5 mmol) Fluorenyl bromide (6.6 g, 38 mM), dicarbonate (97 g, 70 mM) and potassium iodide (100 mg, catalyst amount) were mixed with acetonitrile (250 ml) under a nitrogen atmosphere, and Reflux is hours. The solvent was removed in vacuo and the residue was distributed between ethyl acetate and ammonia (2 M). The layers were separated and the organic layer was dehydrated (MgSCU).眞 2 The solvent was eliminated, and the resulting residue was purified by colloidal flash chromatography using hexane / digas methane 8: 2 as the eluent. The title compound was obtained as an oil. Yield: 7.5 g (98% Ma) 21D + 87〇 (cl, MeOH); EIMS (70 eV) m / z (relative strength) 437 (12, M +, 81Br), 435 (13, M +, 79Br) Production method 18 (R) -2-N, N_dibenzylamino-5_methoxy-8- (4-methylhexahydropyridine 1,2,3,4-tetrahydrofluorene in hydrogen atmosphere , Add N-methyl hexahydro p ratio p wells (5.9 ml, 53 moles) ginseng (monomethylidene propionate) one free (〇) (〇.41, 0.44 mole), (R) _BINAP (0.82 G '1.3¾ mole) with sodium tert-butoxide (0.4 mg, 4.2 mmol) to (R) _8_bromo-2-N, N-dibenzylamino-5_methoxy_ i, 2,3, 'tetrahydropyrene (19 g, 44 mmol) in anhydrous toluene (500 ml). This dark solution was dropped at 85 C for 23 hours, cooled, filtered and emptied. Evaporation. Purified via a silica gel column using NH3 saturated aerosol / methanol (100: 2) as the eluent, yielding 19 g (yield 97%) of a viscous colorless oil · [α] 21〇 + 72 (C = l, chloroform); EIMS (70 eV) m / z (relative strength) 455 (15, MT). 45- ^: The paper size applies the Chinese National Standard (CNS) A4 specification (2 10 × 297 mm) t read first read the back Caution deposit Complete this page)

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-I 1 · I-1 = — I 1 = 568786 A7 _______B7_ V. Description of the invention (43) Preparation method 19 (R) _2 · Amino-5-methoxy · 8- (4-methylhexahydropyridine- (Buky) _1,2,3,4_tetrayfe: -VA * The general method of Lanaide 10, from (R) -2_N, N_diamidino_5-methoxy-8- (4 -Methylhexahydropyridine_1-yl) 1,2,3,4-tetrahydrofluorene to prepare the title compound. Yield: 5.3 g (82%) of a thick, colorless oil: [a] nD + 20. (Cn, chloroform); £ .8 (706 \ ^) 111/2 (relative intensity) 275 (53,) ^ +). Production method 20 5-methoxy-8-nitro-: ι, 2,3,4-tetrahydrofluorene-2-carboxylic acid methyl ester Take 5-methoxy-i, 2,3,4-tetrahydrofluorene Methyl-2-carboxylate (ι · ιgram, 5 mmol) is described in DW Johnson, LN Mander,

Aust. J. Chem. 1974, 8, 1277-1286) was dissolved in acetic anhydride (20 ml) and treated with 70% nitric acid (0.4 ml) at 0 ° C for 1 hour. The mixture was poured into ice water and ether. . The organic phase was separated, evaporated in vacuo, and the residue was triturated with diisopropyl ether to yield 0.27 g (20%) of the crystals of the title compound: mp 100-104 C; EIMS (70 eV) m / z (relative strength) 265 (35, M +). Preparation method 21 5 -Methoxy-8_nitro_1,2,3,4-tetrahydropyrene-2_carboxylic acid, J-Consumer Cooperative Co., Ltd. (for the first time, please read the precautions on the back) #Fill in this page) Take 5-methoxy-8 · nitro_1,2,3,4-tetrahydropyrene_2_carboxylic acid methyl ester (1.9 g '7.1 mmol) and methanol (20 ml ) And 2M NaOH (10 ml) were refluxed for 1.5 hours, and the solvent was evaporated in vacuo. The residue was dissolved in ethyl acetate and acidified. The organic phase was separated, air-dried and evaporated to yield 17 g (95% yield). Crystals: mp (after recrystallization from diisopropyl ether / ethanol) 189_190 T :; EIMS (70 eV) m / z (relative strength) 25 1 (30, M +).一一 一 _ ^^ — _ 46-This paper uses the Chinese National Standard (CNS) A4 size (210X 297 mm) ~ 568786 A7 ---_ _ B7_ V. Description of the invention (44) 'm2 1 (4- Morpholine phenyl) _5-methoxy-8-nitro-1,2,3,4-tetrahydrofluorene_2_carboxamidine " takes 5. · methoxy-8-nitro-1, A mixture of 2,3,4-tetrahydroarsino-2-chinic acid (13 g, 5 hamol), toluene (20 ml) and thionine (8 ml, 25 mmol) at 80 ° C Heat for i hours. The solvent was removed in a vacuum, and the residue was dissolved in dichloromethane (10 ml) and added to 0X: containing 4-morpholinylaniline (89 mg, 5 mmol) and triethylamine (10 g, 10 millimoles) of methane (20 mL). The mixture was stirred at 20 ° C for 2 hours, water was added, and Shen Dian 'was filtered to give 1.9 g (90%) of the crystals of the title compound: mp 25 1-253 〇; £ 1] \ 48 (7〇6 \ ^) 111/2 (Relative intensity) 411 (100,] ^ +). Production method 23 N- (4-morpholinylphenyl) -8 • amino-5-methoxy-1,2,3,4-tetrahydrofluoran-2-carboxamidine Printed by the cooperative (please read the notes on the back before filling this page)

Take N- (4-Mercaptophenyl) _5_methoxy-8-nitro_1,2,3,4-tetraazapine-2 · chitamine (2.05 g, 5 mmol) Heat the solution with sodium dithionite (3.5 g, 20 mmol) in N, N-dimethylformamide (20 ml) and water (2 ml) at 90 ° C for 7 hours. After cooling, the reaction mixture was distributed between water and ethyl acetate. The phases were separated. The organic phase was washed twice with water and evaporated in the air. The residue was triturated with diisopropyl ether / ethyl acetate to give 1.4 g (72% yield). Crystals of the title compound: mp 219-222 ° C; EIMS (70 eV) m / z (relative intensity) 38 1 (70, M +). Preparation method 24 N- (4_morpholinecarbonylphenyl) · 5 · methoxy-8 · nitro-1,2,3,4-tetrahydrofluorene-2-carboxy-47- This paper standard is applicable to Chinese national standards (CNS) A4 specification (210X297 mm) 568786 A7 B7 The member of the Standard Division of Xingdi Ministry-X Consumer Cooperatives Co., Ltd. 5. Description of the invention (4S) The amidine contains methoxy-8 · nitro-1,2 , 3,4-tetrahydropyrene-2-carboxylic acid (1.0 g, 4 mol), toluene (20 liters), N, N-dimethylformamide (10 drops), and sulfite A mixture of thoron (1.5 ml, 22 mmol) was taken at 60. (: Heating for i hours. Remove the solvent by emptying, dissolve the residue in dichloromethane (20 liters), and add it to 5 ° C to contain 4-limyl epimethylpyridylline (820 mg, 4 mmol) Ear, illustrated in 1.?.Dai Wenlin (〇6 ¥ 11! 1) '1. (1; 11 € 111.8〇.,? € 11 ^ 111 ^ 115 1, 1975, 8 3 0-841) and triethylamine (800 mg, 8 mmol) in dichloromethane (30 ml). Expansion at 20 C: After mixing for 2 hours, add water, separate the organic phase, dehydrate and empty to remove the solvent. Oily residue Crystallization from diisopropyl ether / ethyl acetate yielded 1.2 g (73% yield) of the title compound: 1} ^ 186- 189 ° C; EIMS (70 eV) m / z (relative strength) 439 (20 , M +). Production method 25N- (morphocarbonylphenyl) -8 · amino_5_methoxy-1,2,3,4 · tetrahydrofluorene-2 · benzylamine containing N_ (4 · Morpholine carbonylphenyl) _5_methoxy_8-nitro-1,2,3,4-tetrahydrofluorene-2-carboxamide (1.3 g, 2.8 mmol) and sodium dithionite ( A solution of 2.0 g, η mmol) of N, N-dimethylformamide (20 ml) and water (2.5 ml) was heated at 85 C for 3 hours. After cooling, the reaction mixture was distributed Between water and ethyl acetate. The phases were separated. The organic phase was washed twice with water and evaporated in vacuo. The organic phase was dehydrated and evaporated. The residue was treated with diisopropyl ether to yield 3 10.0 g (yield 30%). Crystal of the title compound: EIMS (70 eV) m / z (relative strength) 409 (100, M +). -48- This paper size is in accordance with China National Winter Standard (CNS) A4 specification (2ΐ〇χ297297) ( (Please read the notes on the back before filling out this page) if,-口

Printed by the Consumer Cooperatives of the Bureau of Decisions, Bureau of Standards, Ministry of Economic Affairs 568786 A7 -__—_____ B7 V. Description of the Invention (46) Method 26 (1〇-2-1 > ^ Diamido-5- (1-hydroxyethyl) -8_ (4-methylhexahydropyridine_1 · yl) -1,2,3,4-tetrahydropyrene (R) -5-bromo-2-N, N · dibenzylamino-8_ ( 4_methylhexahydroπ-pyridyl) _1,2,3,4-tetrahydropyrene (1.4 g, 2.8 mmol) is dissolved in freshly distilled tetrahydrofuran (100 ml), and Washed with argon and cooled to (:. To the solution was added a third butyl lithium (2.6 ml, ΐ · 4] ν [pentane solution, 3.7 millimoles), the red solution was stirred at ambient temperature for 10 minutes Add acetaldehyde (320 microliters, 5.7 millimoles), stir the reaction mixture for 10 minutes at the bottom, 2 hours at 0t, and 10 minutes at the main. The reaction was stopped by adding water, and the solvent was evaporated. Residual The material was distributed between ether (100 mL) and 2 M NH3 (20 mL). The aqueous phase was extracted with ether (20 mL). The combined organic layers were washed with brine (20 mL) and dehydrated (MgSCU). The solvent was evaporated, Produced 20 grams of crude product 'through Shixi gel column chromatography Purification using aerosol / methanol / concentrated NH3 (95: 5 ·· 0.5) as eluent yielded 910 mg (yield 68%) of the title compound as a yellow foam: ESI m / z (relative strength) 470 (1〇 〇, M + 1). Production method 27 (R) -2-Amino-5 -ethyl-8- (4-methylhexahydropyridine_Bulkyl tetrazine take (trans) -2- team > ^ -Dibenzylamino-5- (1-hydroxyethyl) -1,2,3,4-tetrahydrofluorene (1.6 g '3.4 mol) was dissolved in acetic acid (80 ml) at 100%. Stir off at 2 ° C for 2 hours. 眞 2 Evaporate the solvent and dissolve the residue in methanol (50 ml). Add palladium (10%) / carbon (600 mg), flush the solvent with nitrogen. Add formic acid to the solution Ammonium (1.7 g, 28 mmol), the reaction mixture was stirred at 65 ° C for 2 hours _ -49- The paper size suitable financial Guanxu standard (CNS) "4 secrets (210X 297 Gongchu-) ----- (Please read the notes on the back first \ ^: Fill in this page)

Member of the Bureau of Standards of the Ministry of Justice, η Consumption Cooperative, printed f 568786 A7 ____B7 V. Description of Invention (47) ^ Temporary. The catalyst was filtered off and the solvent was evaporated in vacuo to give 1.3 g of crude product. The residue was distributed between dichloromethane (120 ml) and 2 M NHb (30 ml). The organic phase was washed with brine (20 mL) and dehydrated (MgS04). The solvent was evaporated in vacuo to yield 740 mg (79% yield) of white semi-crystals of the title compound: eimS (70 eV) m / z (relative intensity) 273 (24, M +). Production method 28 (R) -N- [8- (4 · methylhexahydropyridine · ι_yl) _1,2,3,4_tetrahydro_2_fluorenyl] -4-trifluoromethylphenylhydrazone A solution of 4- (trifluoromethyl) benzamidine chloride (96 mg, 0.46 mmol) in methane (5 ml) was added dropwise to the cold solution containing (R) -2-amino group_8_ ( Ren methyl hexachloride Bijing-1_yl) 1,2,3,4_tetrahydropyrene (110¾ g, 0.44 mmol) and triethylamine (91 μl, 0.66 mmol) Methyl chloride (20 liters) in solution. After the addition, the reaction was stirred at ambient temperature for 15 minutes, and then washed with a dilute sodium bicarbonate aqueous solution. The organic phase was dehydrated (Na2S04) and was evaporated under vacuum. The resulting crude product was purified on a silica gel column using NH3 saturated gas imitation / ethanol (100: 2) as the eluent. Yield: 150 mg (81%) of the title compound as white crystals: mp 203-204 Ό; [a] 21D-20. (C ΐ · 〇, gas imitation); EIMS (70 eV) m / z (relative intensity) 417 (10, M +). Production method 29 (R) -2-N, N_ mono + amino group 5- 5- ¾methyl 8- (4-fluorenylhexahydrogen P ratio p well-1_yl group) _1,2,3,4-tetrahydro Take (R) -5 · bromo-2 · N, N -diamidoamino-8- (4-methylhexahydro p ratio p well small group) · 1,2,3,4-tetrahydrofluorene ( 800 mg, 1.6 mmol) was dissolved in freshly distilled tetrahydrofuran (80 ml), washed with argon, and cooled to -78. In solution (Please read the precautions on the back / fill this page first)

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568786 A7 B7 V. Description of the invention (48 This page was written with the addition of second butyl lithium (1.5 ml, 1.4 M pentane solution, 2.1 mmol). The 'reaction' mixture was stirred at ambient temperature for 10 minutes. Methyl chloroformate (25.0 microliters, 3.2 mmol) was added, and the reaction mixture was stirred at -78 x: for 1 minute at 0 ° C. The reaction was stopped by adding water, and the solvent was evaporated. The residue was distributed in ether (90 mL). ) And 2 M NH3 (15 ml). The organic layer was washed with brine (10 ml); strips, dehydrated (MgS04). The solvent was evaporated to give 770 mg of crude product. Chromatography on a silica gel column using chloroform / Methanol / concentrated NH3 (25 ·· 5: 0.5) as eluent for purification, yielding 60 mg (r) _5_carboxymethyl_2_n, n_monoamido · 8 ((4 " methylhexahydropyridine) Phen-1-yl) -1,2,3,4-tetrahydronaphthalene (containing 13% of the corresponding 5-hydrogen analogue) yellow oil: EIMS (70 eV) m / z (relative strength) 483 (1, M + 1). This methyl ester (6 to 10 mg, 1 "mole) was dissolved in fresh Xiyu tetrahydroxan (35 ml), and Is aluminum hydride (120 mg, 3.1 mol was added) .Reaction mixture at 4 5 C撗; After 2 hours, cool down to room μ. Add water (120 μl), 15% NaOH (120 μl) and water (240 liters printed by the Ministry of Standards and Standards Bureau Shellfish Consumer Cooperative Co., Ltd.) to stop the reaction. Dissolve the slurry for 2.5 hours at room temperature. Filter and remove the precipitate to evaporate the solvent to produce 730 mg of crude product. After passing through a silica gel column, use aerosol / methanol / concentrated NH3 (95: 5: 0.5) as the dissolution. Purification of the solution yielded 36 mg (yield 50/0) of the title compound as a white foam: EIMS (70 eV) m / z (relative strength) 455 (1,); [α] 21〇 + 44. c 〇12, aeroform). Production method 30 (R) -2-Amino-5-methyl-8_ (4-methylhexahydro p-pyridyl) _ι, 2,3,4 · Tetrahydrobranched ( R) -2-N, N-dibenzylamino-5-hydroxymethyl_8_ (4_methylhexahydropyridine) 51 This paper is sized to the Chinese National Standard (CNS) A4 (2l0x297 mm) 568786 A7 B7 printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Distillation 5. Description of the invention (49) based) 1,2,3,4_tetrahydropyrene (360 mg, 0.78 mmol) dissolved in formic acid (35 ml) 'Add surface (10%) / carbon (170 mg), flush with nitrogen Was added ammonium formate in solution A (3 9〇 mg, 6.2 mmol), the reaction mixture was stirred at 65 C 13 h. Vent catalyst addition, air Zhen solvent was evaporated, yielding 220 g of residue love. The crude Wey methyl compound was dissolved in acetic acid (25 ml), and after adding #bar (10%) / (60 mg), the solution was flushed with hydrogen. The reaction mixture was hydrogenated at room temperature and atmospheric pressure for 4 hours. The catalyst was filtered off, more palladium (10%) / carbon (160 μg) was added, and then hydrogenated at room temperature and atmospheric pressure for 24 hours. The catalyst was filtered off and the solvent was evaporated in the air. The residue was distributed between ether (70 ml) and concentrated NH3, and the organic phase was washed with brine (5 ml). The organic layer was dehydrated (MgS04), and the solvent was evaporated in vacuo to yield 120 mg (yield 61%) of white semi-crystals of the title compound: EIMS m / z (relative strength) 259 (20, M +); [a] 21D-1. (C 0 · 09, chloroform). Production method 31 (S) -3-N, N-diamidoamino group · 5-methoxy-3,4 · dihydro-2H-1-benzopyran hydrochloride Take (S) -3-amino group -5-Methoxy-3,4-dirat- 2py-1-benzopyran (45 g, 0.25 mol, described in WO 93/07135), K2C03 (120 g, 0 87 mol ) And fluorenyl bromide (65 ml, 0.55 mol) in acetonitrile (1000 liters) and mixed under nitrogen. The reaction mixture was refluxed for 45 hours. The mixture was purged, and the solvent was removed in vacuo. The residue was distributed between ether and saturated NaCl (aq). The layers were separated and the organic phase was dehydrated (MgS04). After filtration, the hydrochloric acid salt was precipitated at room temperature. Yield · 99 g (99%). Take the analysis sample and turn it into a test: [a] 21D + 116. (C 1.0, gas imitation); EIMS (70 eV) m / z (relative strength) -52- This paper size applies to China National Standard (CNS) A4 (210X297 mm) (Fill in this page)

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568786 Member of the Bureau of Divide Standards _τ Printed by Consumer Cooperatives A7 B7 V. Description of the Invention (50) 359 (28, M +) 〇 Method 32 (S) -3-N, N-Diaminoamino_3 , 4 · Dihydro-2Η · 1-phenylpyranopyrano (S) -3-N, N-Diamidoamino · 5-methoxy_3,4_dihydrodjj ″ The acid salt (67 g, 0.17 mol) was dissolved in methane (500 ml) under nitrogen, and the solution was cooled to -75 ° C. Boron tribromide (32 ml, 0.34 mol) was added dropwise over 5 minutes. The temperature was slowly raised to and the reaction was stirred overnight. The reaction was quenched by carefully adding 2 M aqueous NH3 solution to the reaction mixture. The layers were separated and the aqueous phase was extracted twice with methane. The organic layers were combined, washed with brine, dehydrated (MgS04), filtered and emptied to remove the solvent, resulting in a brown oily residue, which was purified by flash chromatography of residual gels using methane as the eluent. Yield: 50 g (86%) of the title compound: [a] 21D + 109. (C 1.0, chloroform); EIMS (70 eV) m / z (relative intensity) 345 (5, M +). Production method 33 (S) -2- (3-N, N · —fluorenylamino-3,4 dichloro-2 fluorene -1 -private onan · 5 · oxyl) 2-methylpropylamine S) -3_N, N-Dibenzylamino-5-hydroxy-3,4-dihydro-2fluorene-1-benzopyran (50 g, 0.14 mol) dissolved in nitrogen, anhydrous l, 4 -Dioxin (450 ml). Add sodium hydride (60-65% oil, 6.1 g, 0.15 mol) in portions. Mix under the chamber and stir for 1 hour. Added 2-bromo-2-methylpropanamide (24 g, Mol), IGC · Coutts; MR · Southcott J. Chem. Soc. Perkin Trans. 1 1990, 767-77 1) Into a dark green solution, heat and reflux for 3 hours with stirring. Then add sodium hydride (60-65% oil, 2.8 grams, 70 millimoles) and 2-bromo-2-methylpropanamine-53- in batches. This paper applies Chinese national standard (0-5) 6-4 (2) 0 '; < 297 mm) (Please read the method on the back, meaning ¾, and then fill out this page)

568786 Bureau of Standards, Ministry of Economic Affairs__Consumer Cooperatives, Infanches A7 B7 V. Description of the invention (51 (4.6 grams, 28 millimoles), continued heating at 60 ° C for 17 hours. After cooling, add a small amount of methanol (10 ml), the solution was filtered, and the solvent was removed by emptying. The residue was distributed between ethyl acetate (500 ml) and saturated NaHC03 solution (50 ml). The organic layer was dehydrated (MgS04), and the solvent was removed by emptying, resulting in a brown residue. Crystallized from ethyl acetate / hexane. Yield: 45 g (71%) of the title compound as a white solid: mp 133-134 ° C; [a] 21D + 99. (c 1.0, chloroform) '· EIMS (70 eV) m / z (relative strength) 430 (9, M +). 34 (S) -5 -amino-3 -N, N -dimethylamino · 3,4-dihydro · 2H-benzopyrene Add sodium hydride (60-65% oil, 8.5 g, 0.21 mole) in portions under nitrogen to (S) -2- (3-N, N-dibenzylamino-3,4- Dihydro_2Η · 1-phenylpyran-5-yloxy) -2-methylpropanamide (46 g, 0.11 mole) anhydrous N, N-dimethylformamide (45 ml) With 1,3 · dimethyl · 3,4,5,6_tetrahydro_2 (111) -pyrimidone (45 ml) solution. The contents were heated with stirring for 13 hours. The mixture was then allowed to cool and the solution was distributed between ethyl acetate (400 ml) and a 2 M NH3 solution (200 ml). The layers were separated and the aqueous layer was washed with ethyl acetate ( 15 liters) extraction. The combined organic layers were dehydrated (MgS04). Concentrated and concentrated to give a brown oil. EIMS (70 eV) m / z (relative strength) 43 〇 (3, M +). The resulting material (0.11 mol ) Dissolved in ethanol (350 亳 L). 6M6α solution (250ml) was added, and the reaction mixture was heated under reflux for 16 hours. After stirring, the mixture was cooled to 35 ° C, the ethanol solvent was removed by emptying, and ethyl acetate was added to the remaining In aqueous solution, the mixture was cooled on ice, and concentrated Nh3 was added slowly. The layers were separated, and the aqueous layer was extracted with another portion of ethyl acetate. The combined organic layers were dehydrated (MgS04), and the solvent was removed by emptying. (C short silicon tubing column pure C * first read the 意 Λ items on the back before filling this page)

-54 568786 A7 B7 V. Description of the invention (52 Printed by the Central Bureau of Standards of the Ministry of Dispersion, X Consumer Cooperatives (dissolved liquid · · appearance / ethyl acetate · 8 ·? A 〇 < too γ since day, 8 · 2) 25 g (yield 68%) of light yellow oil. The product will slowly crystallize when left standing in a refrigerator = knife analysis. The sample is recrystallized from ether / petroleum ether: mp i 〇i C; [α] D + 123 (c 10 'chloroform); EIMS (70 eV) m / z (relatively strong yield) 344 (17, M). Ding Difan, method 3 (SW- (3-N ， N_Dibenzylamine_3,4_dihydro_2ΗPhenylpyranopyran_5_yl） _4_ Methylhexahydropyridine_2,6_dione with 1,1'-carbonyldiimidazole ( 15.2 g, 93.9 mmol) to a homogeneous solution of anhydrous tetrahydrofuran (575 ml) containing N • methylimine diacetic acid (6.90 g, 46.9 mmol), and the mixture under nitrogen Heat under reflux for 2 hours. Over 05 hours: add (S) -5-amino-3-N, N-dibenzylamino_3,4 · dihydro_2Η_1 phenylpyran (15.0 g, 42.7 millimoles) of tetrahydrofuran (120 liters). The reaction mixture was heated at reflux for 28 hours, then allowed to cool, and emptied. The solvent was removed. The residue was purified on a short silica gel column (eluent: methane and ethyl acetate) to give 14.1 g (71% yield) of the title compound as a pale yellow solid: ] 21D + 89〇 (c 1.〇, aerobic); EIMS (70 eV) m / z (relative strength) 455 (8, M +). Production method 3 6 (8) -3 * ^, > ^ -Dibenzylamino-5- (4-methylhexahydro 17 is called _1_yl) -3,4_digas_ 2H-1 · benzo ppyran-Lithium aluminum hydride (9.30 g , 246 millimoles) to (s) -1_ (3_N, N-dibenzylamino-3,4-dihydro-2H-1-phenylpyran_5_yl) _renmethylhexahydro Pycnogenol-2,6-dione (25.4 g, 55.8 mmol) in anhydrous ether (800 ml-55) This paper is sized for China National Standard Net (CNS) A4 (210 × 297 mm) — ί: -----_ τι (Please read the notes on the back, ^ Issue, and then fill out this page)

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568786 A7 ~ ^ ___ _B7_ 5. Description of the invention (53) '—'-) Stir the solution. The reaction mixture was heated to reflux under nitrogen for 5 to 5 hours, and stirred overnight under a wool / dish. The mixture was cooled (ice bath), water (10 ml), 15% aqueous NaOH (10 ml) and another portion of water (30 ml) were added sequentially. The precipitate was filtered off and washed with several portions of warm tetrafuran. The organic layers were combined and the solvent was removed by emptying. The residue was purified by silica column chromatography (eluent: chloroform / ethanol; 95 · 5 + 5% concentrated NH3) to give 136 g (yield 57%) of the title compound as a pale yellow oil: [a] 21D + 63. (C ΐ · 〇, methanol); EIMS (70 eV) m / z (relative strength) 427 (5, M +). 3 7 (s) -3_Amino-5_ (4-methylhexahydropyridine_1_yl) · 3,4 · Dihydro_2Η · 1 · Benzophane under nitrogen and palladium ( 10%) / activated carbon (0.97 g) and ammonium formate (3 j g, 49 mmol) to (S) _3_N, N_dibenzylamino-5_ (4_methylhexahydropyridine- 1-based) _3,4_ mononitro-2H-1-phenylpyrrolidine (2.6 g, 6.2 mmol) in a solution of methanol (100 l). The reaction was stirred at 50 ° C; stirred and heated overnight. The solution was filtered through Celite® and the solvent was removed by emptying. The residue was distributed between a 2 M NH3 solution (20 mL) and ethyl acetate (100 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (3 X 50 mL). The combined organic phases were dehydrated (NS04) and the solvent was removed by emptying, yielding 1.4 g (89% yield) of the title compound as a pale yellow oil: [a] 21D_15. (C 1 · 0, chloroform); EIMS (70 eV) m / z (relative intensity) 247 (74, M +). Process 38 4 · (4_hexahydro p-pyridone-1-yl) benzoic acid is obtained containing 2 MNaOH (10 ml), 4_ (8_aza · 1,4-dioxaspiro [4,5]- 56- ^, paper size ^ Chinese national standard ((milk) 8 4 specifications (210 father 297 mm)) (Please read the notes on the back to fill in this page first) 、 1Τ

Member of the Central Standards Bureau of the Ministry of Distillation-X Consumer Cooperative Press India 568786 Α7 __ B7 V. Description of the Invention (54) Dec-8-yl) benzonitrile (820 mg, 3.36 mmoles; shown in E, c. Taylor) A solution of JS Skotnicki Synthesis 1981, 8, 606-608) and ethanol (7.5 ml) was heated at reflux for 3 hours. The external heating was stopped and the reaction was stirred at ambient temperature overnight. The ethanol solvent was removed in vacuo, and the residual solution was acidified to pH 4 with a 2 M HC1 solution, and extracted with ethyl acetate (50 ml). The layers were separated, adjusted to pH 6 with 2M NaOH, and extracted with ethyl acetate (50 ml). The combined organic layers were concentrated in vacuo. The solid residue was dissolved in 6 M HC1 solution (10 ml). The reaction mixture was heated at 75 ° C for 2.5 hours and then at 55 ° C overnight. The temperature was increased to 75 ° C for 2 hours, and then the reaction mixture was cooled. The pH was adjusted to 4, and the solution was extracted with ethyl acetate (50 ml). The layers were separated, adjusted to pH 5 and extracted. The combined organic layers were dehydrated (MgS04) 'and the solvent was removed by emptying. The crude product was recrystallized from ethyl acetate to give 300 mg (yield 41%) of yellow crystals of the title compound: mp sintered> 2.5! EIMS (70 eV) m / z (relative strength) 219 ( 100, M +). Production method 39 (S) -3_N, N_monoamido-8-oxo-5- (4-methylhexahydro p ratio p well-1-yl) -3,4-dihydro_2H-1-benzene幷; I Bingan was approved by the Ministry of Standards and Standards BureauΗConsumer Cooperatives India Fan (Please read the notice on the back and then fill out this page) Take (S) -3-N, N-Diaminoamino-5- (4-Methylhexahydropyridine-2H-1-phenylhydrazone-1-pyran (6.9 grams, 16 millimoles) and sodium acetate (! .5 grams, 18 pen moles) were dissolved in Acetic acid (43 ml). To the solution was added iodine monochloride (18 ml, 1 M, 18 mmol), and the reaction mixture was allowed to stir at room temperature and in the shade for 24 hours. 25 ml, M, 25 mmol) and stirred for 3 hours. The solvent was evaporated and the residue was distributed between dichloromethane (800 ml) and 2M NaOH (120 ml). The aqueous phase was dichloro_______ -57- This paper is in accordance with China National Standards (CNSyA4 regulations; ^ ------ 568786 Α7 Β7) V. Description of the invention (55) Methane (100 ml) is extracted, and the combined organic layer is brine (2 x 1〇). Washing and dehydration (MaS04). Evaporation of the solvent yielded 86 g of crude product. Using a silica gel column method, using ethyl acetate. Ethyl ester / ethanol (saturated with NH3) (25: 丨) was purified as an eluent to yield 4 "g (43% yield) of the title compound (yellow solid containing about 7% dimer: EIMS (70 eV) m / z (relative strength) state (15, M +). The product was used in the next step without further purification. Preparation method 40 (S) -8-Chimethyl · 3 · N, N_diτamino_5_ ( 4_methyl hexahydroton p well small base 3'4-_ gas-2H-1-Benzene onan is printed by (S) -3-N, N-II芊 Amine_8_iodine 4_methylhexahydropyridine—Buyl) · 3,4-monohydro-2H-1-phenylpyran (2 · 6 g, 4 · 8 mmol) In n, n-dimethylphosphonium amine (100 ml), flush with carbon monoxide. To the solution was added palladium acetate (110 mg, 0.48 mmol), 3, bis (diphenylphosphino) propane ( 2000 g, 0.48 mol), methanol (25 ml) and triethylamine (33 ml, 24 mol). The mixture was reacted with carbon monoxide. (: And reacted under normal pressure for 8 hours. The solution was filtered, and the solvent was evaporated. The residue was co-existed with xylene (2 x 5 (ml)) and distributed in dichloromethane (300 mmol). ) And 2 μNΗ3 (50 ml). The aqueous phase was extracted with methane (50 ml) and the combined layers were washed with brine (2 x 50 strokes) and dehydrated (MaS04). The solvent was evaporated to yield 4.0 G of crude product. Purified by silica gel column chromatography using dichloromethane / ethanol (saturated with ammonia) (50 ••) as the eluate, yielding 7 g (68% yield) of the title compound (containing about 5 % Corresponding 8-H analog) as a yellow solid: EI] vfs (70 eV) m / z (relative intensity) 485 (8'M +). The product was used in the next reaction without further purification. —It ^ _____ -58- The size of this paper is suitable ^ 7 ^^ quasi (—) 7¾ (2Κ) χ7 ^ 5687 Printed by the Consumers Cooperative of the Central Standards Bureau of Didi Ministry 568786 A7 • _____ 5. Description of the invention (56) ~~ jj to 41 (S) -3-N, N-dibenzylamino · 8-hydroxymethyl_5_ (4 · methylhexahydropyridyl) _ 3,4-diazine-211-1-phenylhydrazone 1? Bran take (S) -8-carboxymethyl-3-N, N_dibenzylamino · 5_ (4-methylhexahydropyridine-butyl) -3,4-dihydro_2Η- 1-Benzamidine (49 mg, 100 mmol) was dissolved in anhydrous tetrahydrofuran (40 ml), and lithium aluminum hydride (76 mg, 2.0 mg) was added in portions. The reaction mixture was stirred at 450 ° C for 4 hours and cooled to room temperature. Water (76 µl), 15% NaOH (76 µl) and water (225 µl) were added to stop the reaction 'and stirred for 18 hours. The white precipitate was filtered off and the solution was dehydrated (Mas04). The solvent was evaporated to give 520 mg of crude product. Purified via silica gel column using chloroform / ethanol (saturated with ammonia) (15: υ as eluent, yielding 39 mg (yield 85%) of the title compound (containing about 8% of the corresponding 8-methyl analogue) as a yellow oil. : EIMS (70eV) m / z (relative strength) 457 (15, M +). Production method 42 (S) -3 · amino-8-methyl-5 (4-methylhexahydroρ) Phen-1 _Group) _3,4 · Dihydro-2Η-1 -Benzoxanthenan (External 3-Team > 1-Dibenzylamino-8-hydroxymethyl-5- (4-methylhexahydropyridine) -1-yl) -3,4-dihydro-2H-1-phenylhydrazone (420 mg, 0.90 mmol) was dissolved in methanol (60 ml), and ammonium formate (460 mg, 7.3 mmol) was added (Ear). The solution was flushed with nitrogen, and palladium / carbon (120 mg, 10%) was added. The reaction mixture was stirred at 50 ° C for 16 hours. The catalyst was filtered off, and the solvent was evaporated while emptying to yield 260 mg of crude product. In acetic acid (50 ml), palladium / carbon (120 mg, 10%) was added. The reaction mixture was hydrogenated at room temperature and atmospheric pressure for 46 hours. The solvent was removed by filtration, the solvent was evaporated and the residue was distributed in ethyl acetate ( 120ml) -59-~ ^, paper size is applicable to China National Standards (CNS) A4 specifications (2 丨 0 X297 mm) (Please read the notes on the back ¾ before filling out this page) Order 568786 A7 ------- B7 ----- | __ _--V. Description of the invention (57) and 2 M Between NaOH (10 mL), the aqueous phase was extracted with ethyl acetate (10 mL). The combined organic phases were washed with brine (5 mL), dehydrated (MaS04), and evaporated to give 200 mg of crude solvent. The product was purified by silica preparative TLC using chloroform / ethanol (saturated with NH3) (10: 1) as the eluent to give 150 mg (yield 64%) of the title compound as an oil: EIMs (70eV) m / z (relative strength) 261 (100, M +). Emperor method 43 8-methoxy · 5-nitro-3,4-dihydro-2H-1-phenylpyran-3-ethyl dicarboxylic acid drop Add 65% HNO3 (2.0 ml) to OX: containing 8-methoxy-3 4_digas-2Η · 1 · benzene, p-biran_3_carboxylic acid ethyl @ Purpose (5.5g, 23 millimoles; illustrated in s_0 'Thorberg et al., Acta pharm suec, 1987, 24 (4), 169-182) in a stirred solution of dioxane (50 ml). The solution was Stir at room temperature for 2 hours and wash with water. The organic phase is dehydrated and the solvent is evaporated in vacuo. Diisopropyl ether (30 ¾ liters) ) And ethyl acetate (5 ml) were used to treat the residue, resulting in 15 g (5.3 mol) of 6-nitro isomer crystals. The mother liquor was purified by column chromatography using diisopropyl ether eluent to yield 1.3 g (yield 20%) of the title compound: mp 66-68 ° C; EIMS (70 eV) m / z (relative strength) 28 1 (100 Member of the Central Standards Bureau of the Ministry of Economic Affairs and Consumer Cooperative Press (please read the notes on the back ^ before filling out this page) M +) 〇Method 44 8-methoxy-5 · nitro-3,4-dihydro- 2Η-1-Benzopyran-3_carboxylic acid is taken to contain 8-methoxy-5-nitro-3,4_dihydro-2Η-1-phenyl 幷 ρbiran-3 -fatty acid ethyl ester ( A mixture of 5.8 g, 21 mmol) of ethanol (150 ml) and 2M NaOH (15 ml) was heated to reflux for 30 minutes. The solvent was evaporated and the residue was dissolved in water. After being converted to pH 2 'Ethyl acetate is used to evaporate the air. -60- This paper size applies the Chinese National Standard (CNS) A4 specification (210X 297 mm). Printed by members of the Central Standards Bureau of _χ Consumer Cooperative. 568786 A7 ---____ B7_ V. Description of the invention (58) ^ Solvent yielded 4.9 g (94% yield) of the title compound: mp i81_183; EIM; S (70 eV) m / z (relative strength) 253 (55, M +). Preparation method 45 N- [4- (4-morpholinyl) phenyl] | methoxy_5_nitro_3,4 dihydropyridine sangan-3-folded amine added thionyl chloride (3.6 Ml, 50 mmol) to toluene containing 8_methoxy_5_chryl-3,4-dihydro-2H_1-phenylpyran-3-ol (2.5 g, 10 mmol) (40 ml) with N, N-dimethylformamide (1 ml) in solution. The reaction mixture was refluxed for 2 hours and emptied to remove the solvent. Residual fluorene-based gas was added to 4- (1-morpholinyl) aniline containing fluorene · 78 g, 10 mmol, illustrated in jp Devlin et al., J. Chem · Soc. Perkin Trans, 1 1975 830-841) and diethylamine (2.0 g, 20 mmol) in a solution of dichloromethane (30 ml) were taught for 10 minutes at 0 C and 1 hour at room temperature. The solvent was removed under reduced pressure, dissolved in ethyl acetate, and washed with 2 M NaOH. The solvent was evaporated in vacuo to yield 1.5 g (36% yield) of white crystals of the title compound: mp238-24 ° C; EIMS (70 eV) m / z (relative intensity) 413 (5, M +). Production method 46 N- [4- (4-morpholinyl) phenyl p- 5-amino-8-methoxy-3,4-dihydrophenylpyran-3-carboxamide added sodium monothionite (2.1 g , 12 millimoles) in water (5 ml) to 1 ^-[4_ (4_morphoyl) phenyl] -8-methoxy-5_nitro-3,4_dihydro · 2Η · Benzylpyran-3-carboxamide (1.2 g, 2.9 mmol) in N, N-dimethylformamide (10 ml) is dissolved. Mix at 55 ° C and stir for 3 hours. Empty the solvent and drain. The residue was subjected to silica gel column chromatography, using ethyl acetate as the eluent. Back: Fill in this page if you want to support yourself, 1T

568786 A7 B7 V. Description of the invention (59) ^ Printed and purified by the Central Department of the Ministry of Commerce, Associate Bureau Member, and Consumer Cooperative, yielding 273 g of the title compound (yield: 55%): ειμ§ (70%) m / z ( Relative intensity) 383 (100, M +). Was the exemption of 5-HTib including the anti-fungal method 1 (R) _N_ [8-〇hydropyridin-1-yl) _1,2,3,4_tetrahydro_2 • fluorenyl] _4? Phenanthroline is added difluoroethane (3 liters) to the icy containing (r) _n-the third butoxyfluorenyl hexahydropyrine-1-yl) -1,2,3,4 · tetrahydro- 2-Amidino] -4-morpholinylphenylcarboxamide (1.0 g, 2 mmol) in digas methane (100 liters). The reaction was stirred at ambient temperature for 7 hours. The solvent was evaporated and the residue was dissolved in water (20 ml), basified with 2 M aqueous sodium hydroxide solution, and extracted twice with dichloromethane. The phases were separated and the combined organic phases were dehydrated (N ^ SO4), filtered and evaporated in vacuo. Purified through a gel column using chloroform / methanol / concentrated ammonium hydroxide (95: 5: 0.5) as the eluent to produce 580 mg (yield: 70〇 / 〇) of the title compound as white crystals: nip 202-203 X: KD-56. (C U, gas imitation); E · (70 eV) _ (relative intensity) 420 (5, M +). Example 2 (R) _N- [8_ (4-Ethylhexahydropyridine);! _ Radical ^^, hydrazine tetrahydro- ^ hydrazolium 4 phenylhydrazine and potassium carbonate (44 ml, 0.32 Millimoles) and iodoethane (26 microliters, 0.32 millimoles) to ⑻_Ν_ [8 · (hexahydro ^ well small base 2-fluorenyl] _4_morpholine phenylhydrazine (90 mg, 〇21 亳(Mole) in acetone (20 ml) solution, the reaction was expanded at ambient temperature for 48 hours. The reaction mixture was purged, and the solvent was evaporated. The residue was distributed between methylene chloride and water, and the phases were separated, -62 -Long paper Chinese National Standard (CNS) A4 specification (27 ^ 29_ (please read the method on the back ~ Yishiga before filling this page)

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568786 A7 B7 After the Ministry of Standards and Standards Bureau of the People's Republic of China Ηprinted by the consumer cooperatives V. Description of the invention (60) Organic phase dehydration (NSO4) 'filtration' and 眞 2 evaporation. Purification of the gel column using a gas imitation / ethanol (saturated with NH3) (100: 3) as the eluent, yielded 63 g (yield 66%) of the title compound as white crystals: mp 204-206; (c 1.0, chloroform); EiMS (70eV) m / z (relative strength) 448 (21, M +) 〇 Example 3 (R) -N- [5-methoxy-8- (4 · methylhexahydro Pyrhen-1-yl) β1,2,3,4_tetrahydro-2_fluorenyl] -4-morphenazolamine is added with 1, Γ-carbonyldiimidazole (0.76 g, 4.8 mmol) to 4 Morpholine benzoic acid (0.92 g, 4.5 millimoles; illustrated by J. Degutis; L. Rasteikiene; A. Degutiene ^, Zh. 〇rg · Khim. 1978, 14 (10), 2060-2064) in anhydrous N N-dimethylformamide (75 liters); the reaction was heated at 7 5 C. When carbon dioxide ceases to be released (after 45 minutes), the reaction is cooled to room temperature, and (R) _2_amino-5-methoxy_8- (4-methylhexahydropyridine_1_yl) is added. · 1,2,3,4 · A solution of tetrahydrofluorene (1.2 g '4.2¾ mole) in anhydrous v, N-dimethylformamide (20 ml). The reaction was stirred at ambient temperature for 48 hours, and the solvent was evaporated in the air. After being purified by a gel column using a gas imitation / methanol / concentrated rat ammonium oxide (180: 5 ·· 0 · 5) as the eluent, it was recrystallized from ethyl acetate and a few drops of methanol to produce 1 · 〇. G (yield 53%) white crystals: mp 237-238 X:; [a] 21D-40〇 (C = 1, chloroform); eims (70 eV) m / z (relative strength) 464 (5, M + ). Example 4 (R) -N_ [5-Ethyl-8- (4-methylhexahydropyridine-1-ylbu ^ 'tetrahydro- ^ fanyl] -4_morphenazine (please read first (Notes on the back ¾ then fill out this page)

1T -63- 568786 A7 B7 V. Description of the Invention (61) ^ a " Take 4-morphobenzoic acid (64 mg, 0.31 mmol) and dissolve it in anhydrous N, N_dimethyl; formamide (1 Ml), 1,1'-carbonyldiimidazole (52 mg, 032 mmol) was added. The reaction mixture was stirred at 75 ° C for 1 hour and cooled to room temperature. Add (R) -2-amino-5-ethyl · 8- (4-methylhexahydropyridine] -yl) _1,2,3,4 · tetrahydrobenzene (80 mg, 0.29 Mol) of anhydrous N-dimethylformamide (3 ml) solution, and the reaction mixture was allowed to fall at room temperature for 14 hours. The solvent was evaporated and the residue was emptied and dried. The crude product was purified by preparative Tlc using chloroform / methanol / concentrated NH3 (95: 5: 0.5) as eluent to yield 85 mg (59% yield) of the title compound as a white solid: ton η4% (decomposed) £ 1 乂 8 (7 (^ 乂) 111/2 (relative strength) 462 (27, 馗 +) _, [〇 ^ 21〇-48. (. 0 09, chloroform). Example 5 (R) -N ·!; 5 · Ethyl-8- (4-methylhexahydropyridine_1_yl) _1,2,3,4_tetrahydro_2_fluorenyl]-(4-morpholinecarbonyl) phenylhydrazone Amine was taken by the Ministry of Standards and Standards Bureau of the Ministry of Li-T-Consumer Cooperatives to take 4_morpholinyl benzoic acid (180 mg, 077 mmol); illustrated in] Med. Chem. 1994, 37 (26), 4538- 4554) and ^, carbonyldiimidazole (130 mg, 0.80 mmol) was dissolved in anhydrous dimethylformamide (3 ml), stirred at 75 ° C for 2 hours, cooled to room temperature, then added Anhydrous N, N_dimethyl with (R) _2_amino-5-ethyl-8- (4-methylhexahydropyridine, kernel tetrahydronaphthalene (200 g, 0.73¾ mole) Formamidine solution, the reaction mixture was stirred for 60 hours. The solvent was evaporated in vacuo and the residue was distributed between dichloromethane = (60 ml) and 2 MNH3 (5 ml). Organic phase Brine (10 ml a) was washed and dehydrated (NaaSO4). The solvent was evaporated in vacuo to give 36 mg of crude product. Silica gel column chromatography was performed using chloroform / methanol / concentrated Nips: $ 屋 -64-in the drip section The Bureau of Standards and Standards bears the print of consumer cooperatives 568786 A7-~ ---——___ B7 V. Description of the invention (62) '-〇.5) Purification of Ma Rongxinxin yielded 24 mg (65% yield) of the title compound White solid: mp 213-214 X:; EIMS (70 eV) m / z (phase gamma (27, M +); [a], 28〇 (c〇15, chloroform). Also) Example 6 (仏~ [5-Methoxy_8_ (4 · methylhexahydropyridin_1_yl) -1,2,3,4, methylsulfenyl] -4-morpholinecarbonylbenzidine diamine production method 16 The general method is to prepare the title compound from (R) _2_amino_5_methoxy ^ gas'syl κ hydropyrine-1. Keto tetrahydropyridine. Gas chromatography / methanol / concentrate was used on a silica gel column. Sodium hydroxide (96: 4 · _〇3) was purified as an eluent and recrystallized from ethyl acetate / ether to yield 93 mg (yield 52 // white crystals: mp 209-210 ° C; [a ] 21D-18. (C = l, aerodynamics); EIMS (70 eV) m / z (relative intensity) 492 (π, M +). Examples 7 (feet) _1 [5_bromo_8- (hexahydropyridine__1_yl) _12,34_tetrahydro_2 ^ yl] _cardiomorpholine benzylamine Add trifluoroacetic acid (0.7 ml) to ice cold Containing (r) -n_ [5-bromo_8_ (4-tert-butyloxycarbonylhexahydropyridine_i_kibubenzene] tetrahydromono-fluorenylbumorpholine benzidine (150 mg, • 26 millimoles) in a solution of methane (20 liters). The reaction was stirred at ambient temperature for 20 hours. The solvent was evaporated in vacuo, and the residue was dissolved in water (20 ml) and tested with a 2M aqueous solution of steel hydroxide, and extracted with methane. The phases were separated and the organic phase was dehydrated (NhSOj, filtered and evaporated in vacuo. The residue was purified by silica gel column using chloroform / methanol / concentrated ammonium hydroxide (90 ·· 10: j) as the eluent. Yield: 94 mg (72 %) White crystal: mp 228_229 ° C; [〇c] 21D-6. (C = 1, chloroform); EIMS (70 eV) m / z (relative strength -65- This paper standard is applicable to Chinese National Standard (CNS)) A4 specifications are clear) ----—- (Please read the notice on the back before filling in this page)

Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 568786 A7 B7 V. Invention Description (63) 498 and 500 (1.5, M +). Example 8 (Chem) Hepta- [5-bromo-8- (4-methylhexahydropyridin-1-yl) _1,2,3,4-tetrahydro-2-amidino] -4 · morpholinobenzene The general method of amidine according to method 16 is from (r) _2 · amino-5 · bromo-8- (4-methylhexahydropyridin-1-yl) -1,2,3,4-tetrahydropyrene The title compound was prepared. Purified via a silica gel column using chloroform / methanol / concentrated ammonium hydroxide (95: 5: 1) as the eluent, yielding 100 mg (62% yield) of white crystals: mp 245-246 ° C; [a] 21D-23 ° (c = l 'aerodynamic simulation); EIMS (70eV) m / z (relative intensity) 512 and 514 (1, M +). Example 9 (feet) -fluorene [5-bromo-8- (4-methylhexahydropyrine-1-yl) -1,2,3,4-tetrahydro-2-fanyl] _4_trifluoromethyl Phenyl benzamine is (R) -N_ [8- (4 · methylhexahydropyrine-1-yl) _1,2,3,4-tetrahydro_2-naphthyl difluoromethyl benzamine ( 80 mg, 0.19 mmol) and sodium acetate (200 g) were dissolved in acetic acid (3 ml), and the mixture was stirred at room temperature. Bromine (34 g, 0.2 mmol) was added dropwise to the reaction mixture, and the mixture was stirred at ambient temperature for 2 hours, and 2 M sodium hydroxide solution (100 mL) was added to the reaction mixture with ether (2 X 50 Ml) extract the mixture. The combined organic phases were dehydrated over anhydrous sodium sulfate, filtered, and concentrated. Purification by Shixi gel column using digas-methanol / ethanol (saturated with Nη3) (94: 6) as eluent yielded 80 mg (yield 85%) of the title compound as a white solid: mp 229-230 ° C; [ a] 21D-5.4. (C = l, aerodynamic simulation); EIMS (70eV) m / z (relative intensity) 495 and 497 (3, M +). ____- 66-The size of this paper is appropriate / National Standards (CNS) A4 specifications (丨 (Please read the note on the back? Matters to complete this page)

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568786 Member of the Central Bureau of Standards of the People's Republic of China, printed by the τ Consumer Cooperative, V. Description of the invention (Example (R) -N- [5-methyl-8- (4-methylhexahydropyridine, tetrachloro | fanyl) 4-Morpholine benzamidine ', 4-morpholine benzoic acid (92 mg, 0.44 mol) was dissolved in anhydrous n, n-dimethylformamidine (2 ml) and flushed with nitrogen To the solution was added carbonyl diimidazole (76 mg, 0.47 mmol), and the reaction mixture was stirred at 75 ^ for 1.5 hours. The solution was cooled to room temperature, and dissolved in anhydrous ν, ν_ (R) _2_Amino-5_methyl_8_ (N-methylhexahydropyridine_4_yl) -1,2,3,4-tetrahydro in dimethylformamide (2 ml) Benzene (110 mg, 42 mmol). The solution was stirred at room temperature for 30 hours. The solvent was evaporated in vacuo to give 290 mg of crude product. Preparative TLC on silica gel using chloroform / methanol / concentrated NH3 (95 :: 0.5) Purification of the eluate yielded 145 mg (73% yield) of the title compound as a white solid: mp > 231. (: (decomposition); EIMS (70 eV) m / z (relative strength) 448 ( 3, M +); [a] 21D-60. (C 0.15, chloroform). Example 1 1 N- (4_ Phenylphenyl) _8_ (4_methylhexahydropyridine) _5_methoxy ", ^ rentetrahydropyridine-2-carboxamidine, which contains ^ qi morpholine phenyl ^ heart amine ^-a Oxygen- 丨 Yiyiren tetrahydrofan · 2-carboxamide (1.4 g, 3.5 mmol), bis (2-chloroethyl) _methylamine hydrochloride (96 g, 5 mmol) ) And a solution of sodium bicarbonate (420 mg, 5 mmol) in n-butanol (30 ml) were heated at 90 ° C for 5 hours. After cooling, 2 M ammonium hydroxide (30 ml) was added, and the mixture was heated at 50 ° C.丨 hours. Phase separation, evaporating in the air, purified by silica gel chromatography using chloroform / ethanol / concentrated ammonium hydroxide 90/10 / 0.3 as the eluent. Yield: 32〇mg title-67- this paper rule; Kind of standard (CNS) A4 specification (21 () χ297: (Please read the note on the back · ^ Matters 〃 before filling out this page} «P clothing · 11

V 568786 A7 B7 V. Description of the invention (65) Compound: mp 230-232 ° C; EIMS (70 eV) m / z (relative strength) 464 (75, M +) 〇 (Please read the precautions on the back first ') Fill in this page) N- (4-morpholinecarbonyl) -8_ (4-methylhexahydropyridyl) _5_methoxy ^ 2,3,4-tetrahydrofluorene-2-carboxamide enantiomer Chromatographic preparation of isomers was printed by a member of the Central Standards Bureau of the Ministry of Distillation and Consumer Cooperatives to obtain N- (4-morpholinyl) -8- (4-methylhexahydro p ratio p well) -5-methoxy 1,2,3,4-tetrahydrofluorene-2-carboxamide (5 mg) was dissolved in 4 ml of acetonitrile with pH 3.0 sodium phosphate buffer solution μ = 0.1 (62.5 · 37 · 5 , V / v). This solution was purified on a Nucleosil 7 C18 column (25 X 250 mm) using the mobile phase described above to remove the last dissolved impurities. Collect the main components and dissolve them, and concentrate under reduced pressure at 35-39 ° C. The residue was dissolved in 30 ml of a dissolving solution composed of 10 mM ethylammonium 'diethylamine and acetic acid (4000 + 2 + 2, v / v / v, pH 5.26), and composed of N- (4-morpholinephenyl). Enantiomer of -8- (4 · methylhexahydropyridyl) -5-methoxy-1,2,3,4-tetraazepine-2 -benzylamine in Chiral AGP On a semi-rigid column (10 x 150 mm), a guarded semi-rigid column with the same stationary phase was used to perform a palm-on-half preparation. The flow rate used was 2.0 ml / min and the detection was performed at 260 nm. The separated fractions of the two enantiomers were collected and concentrated under reduced pressure at 35-39 ° C to a volume of about 5 ml. The concentrated fractions were adjusted to pH 10-1 with 5 M NaOH, extracted with aerosol, and the two organic phases were washed with water and dehydrated with anhydrous magnesium sulfate. After filtration through glass wool, the organic filtrate was evaporated in the air to produce two enantiomers as a pale yellow solid. Example 12 N- (morpholinecarbonylphenyl) -8- (4-methylhexahydropyridine-1-yl> 5-methoxy-1,2,3,4-tetrahydrofluoren-2-yl complex Amidoamine contains N_ (morpholinecarbonylphenyl) -8-amino-5-methoxy-1,2,3,4-tetrahydropyrene — _ _ -68- This paper size applies to Chinese national standards (CNS ) A4 size (2 × 297 mm) 568786, description of the invention (bright) 2-carboxamide (280 mg, 0.69 mmol), bis (2-chloroethyl) _methylamine hydrochloride ( 190; mg, ΐ · mmole) and sodium bicarbonate (84 mg, 10 mmole of n-butanol (20 ml)) was heated at 90 t for 5 hours. After cooling, 2M ammonium hydroxide (10 Ml), and the mixture was heated at 50 ° C for 1 hour. The organic phase was evaporated in vacuo, and the residue was purified by silica gel chromatography using chloroform / ethanol /; hydrazine masked 9 0: 1 0: 0.5 as the eluent. Yield: 60 mg (1 §%) of the title compound: EIMS (70eV) m / z (relative strength) 492 (50, M +). Example 13 (S) _N- [5_ (4-methylhexahydropyridine) Geng- ^ yl) _3,4_dihydrobenzopyran_3-yl] -4-morpholine benzylamine contains 4-morpholine benzoic acid (380 mg ,! 83 millimoles; illustrated in j Degutis; L. Rasteikiene; A Degutiene 'Zh. Org. Khim. 1978, 14 (10), 2060-2064) and l, r-carbonyldiimidazole ( 310 mg, 1.92 millimoles) of anhydrous dimethyl methylamine (12 ml) solution was stirred at 75 ° C for 30 minutes. After the mixture was cooled to A temperature, (S) -3 -amine group_5 was added -(4_methylhexahydrogen P ratio ρ well-based) · 3 4_ monooxy_2H-1-phenylamidine leaf t; an (430 mg, 1.74 mmol) ν, N-dimethylformate through the center of the mantle Standard Bureau Member_τ Consumer Cooperative Solution for Indiraben (8 ml). The reaction mixture was stirred at room temperature for 3 days. Another portion of 1,1'-carbonyldiimidazole (57 mg, 0.35 mmol) was added. The mixture was stirred for another 3.5 hours. The solvent was removed by emptying and the residue was purified by silica gel column chromatography (eluent: chloroform / ethanol 93: 7 + 0.5% ΝΗ3) to give 513 mg (yield 68%) of the title compound. White solid: mp 21〇_2U. (:; [A] 21D-145. (C 1.0, chloroform); EIMS (70 eV) m / z (relative strength) 436 (65, M +). -69- This paper size applies to China National Standard (CNS) A4 specifications ( 210X297 mm) 568786 A7 B7 Member of the Central Standards Bureau of the Ministry of Economic Affairs of the People's Republic of China-T-Consumer Cooperative Association ) -3,4-dihydro · 2Η_; μphenylpyranone_3-yl] · 4 · (4-hexahydropyridone-butyl) benzidine, containing 1,1, '-carbonyldiimidazole ( 116 mg, 0.0016 mmol) and 4 _ ('hexahydropyridone-1-yl) benzoic acid (150 mg, 0.683 mmol) of anhydrous N, N-dimethylformamide (5 Ml) solution was stirred at 75 ° C for 50 minutes. The mixture was cooled and ν Ν-containing (S) -3-amino-5 · (4-methylhexahydropyridine-2Η-1-phenylhydrazone) was added (161 Aike, 0.651 mmol). Dimethylmethaneamine (4 ml) solution. The reaction mixture was stirred at room temperature for $ days. The solvent was removed by emptying and the residue was purified by silica gel column chromatography (eluent: chloroform / ethanol 90 · 10+ 0.5% Concentrated NH3), yielding 54 mg (yield 19%) of the title compound as a white solid: mp 222-225 ° C (decomposition); [0 ^ 221) 436. (C 0.30, chloroform) · TSPMS (70 eV) m / z (relative strength) 449 (Μ + 1) 〇 Example 15 (S) -N- [8-methyl_5- (4_methyl-hexahydro Leaves t; p well-1_yl) _3,4_ dihydro-2Η-1-phenylpyran-3-yl] -4- (dimethylaminecarbonyl) benzidine to 4- (dimethylaminecarbonyl) Benzoic acid (A.T. Jurewicz); U.S. Patent 3,607,918,1971 (38 mg, 0.20 mmol) and M, · carboxydiazole (34 mg, 0.21 mmol) are dissolved in anhydrous N In dimethylformamide (4 ml), stir at 75 ° C for 1.5 hours. The reaction mixture was cooled to room temperature '(S) -3 -amino-8-methyl-5- (4-methylhexahydrogen π ratio p well group) _3,4_ dihydro-2H-1-benzene A solution of p-biran (49 mg, 0.19 mmol) in anhydrous n, N-dimethylformamide (5 ml). The reaction mixture was stirred at 50 ° C for 14 hours -70- This paper size applies to Chinese National Standard (CNS) A4 (210X297 mm) " ----- (Please read the note on the back; please fill in this later page)

1T 568786 A7 ---- B7 V. Explanation of the invention (68) When the solvent is emptied, 120 mg of crude product is produced. Purified by preparative TLC using chloroform / methanol / conc. NH3 (95: 5: 0.5) as eluent to yield 40 mg (yield 48%) of the title compound as a white foam: EIMS (70 eV) m / z (relative intensity) 436 (26, M +); [a] 21D-9. (C 0.20, chloroform). t η ΐ6 Ν_ [4 · (4_morpholinyl) phenyl] · 8-methoxy · 5- (4 · methyl-hexahydropyrine-1-yl) -3,4-diwind-2Η -1-Benzamidine? Bran-3-Epioxamine contains 1 ^-[4- (4-Molyl) phenyl] _5-amino-8-methoxy-3,4-dihydro_ 2Η-1-Benzamidine-3-benzidine (270 mg, 0.7 mmol), bis (2-ethylethyl) methylamine hydrochloride (288 mg, 1.5 mmol) and sodium bicarbonate (126 mg, 1.5 mmol) of n-butanol (10 ml) in 90 °. (: Stir for 2.5 hours. Add 2 M ammonia (10 ml) at 50 ° C. The mixture is cooled and the phases are separated. The organic phase is evaporated and the residue is subjected to silica gel column chromatography using ethyl acetate / Triethylamine (100: 8) was purified by dissociation and produced 170 mg (yield: 50%) of white crystals of the standard compound: nip 202-204 ° C; EIMS (70 eV) m / z (relative strength) 466 (100 , M +). Example 17 Seal 4 (foot) of the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs of Yijing- > ^-[8_ (4-methylhexahydro-1? Bikou-1-yl) -1,2 , 3,4_tetrahydro_2-fluorenyl] -4- molybdenum, added 1,1'-pyridyl bisamido (0.73 g, 4.3 mmol) to 4_molyl Formic acid (0.89 g, 4.3 millimoles; illustrated by J. Degutis; L. Rasteikiene; A. Degutiene, Zhi Org. Khim. 1978, 14 (10 ), 2060-2064) Anhydrous n, N-dimethylmethyl-71-This paper size applies Chinese National Standard (CNS) A4 (210X 297 mm) '----- 568786 A7 B7 V. Description of the invention (69) Lift) in solution; the reaction is heated at 75 ° C. When carbon dioxide stops for _8_1 f minutes), the reaction is cooled to room temperature, and (R) -2 · amino-containing stem JL, fluorenyl, and hydropyridyl) _1,2,3,4-tetralin 1.0 g, 4 "milliliter) of anhydrous N, N-dimethylformamide (5 ml) solution. Reaction at ambient temperature: Stir for 24 hours, evaporate the solvent in the air. Purified via a silica gel column using aerosol / methanol / concentrated hydroxide (95 ·· 5: 0.5) as the eluent to produce 5 g (yield = 85 / 〇) of the title compound as white crystals: Qing i; [ a] 21D_49. (C κο, chloroform); EIMS (70 eV) m / z (relative intensity) 434 (10, M +) 〇 Pharmacological test method ⑴ Functional h5_HT1B receptor assay To evaluate the 5-HTib receptor Antagonistic properties, the standard analysis method for the electrical stimulation of [3H] -5-HT released from the occipital cortex of guinea pigs. Materials and methods Buffer composition (mM) NaHCCK (25), NaH2P04 · Η20 (ι · 2), NaCl (117), KC1 (6), MgS04x7H20 (1.2), CaCl2 (l.3) Printed from the Consumer Bureau of the Associate Bureau, EDTA Na2 (0.03). Ventilate the buffer for at least 30 minutes before use. The pH of the buffer was about 7.2 at room temperature, but rose to about 7.4 at 37 ° C. Preparation method of occipital cortical slice

Guinea pigs (200-250 g) were killed by decapitation and the whole brain was removed. The occipital cortex was cut and sliced into 0.4 x 4 mm slices using a Mcllwain microtome. Before cutting, carefully remove the white part of the tissue with forceps. Sections were cultured in 5 ml of rinsing solution containing 5 rnM of methylpropylbenzyl chloride. And 0.1 mM -72- This paper size is applicable to the Chinese National Standard (CNS) A4 specification (210X297 mm) 568786 Member of the Central Standards Bureau of the Ministry of Economics, printed meal A7 of χ Consumer Cooperatives --____ — __ 5. Description of the invention ( 70) After incubation with [H] _5ht for 30 minutes, the sections were transferred to test tubes, washed with an equal volume of buffer solution, and washed 3 times. The sections were transferred to a super-perfusion chamber with a plastic dropper and buffered with a absorption inhibitor citalopram (2.5 μM) at a flow rate of 0.5 liters / minute for 40 minutes. Electrical stimulation released by ϋίχ Super perfusion buffer was collected every 2 ml, and the 4th and 13th dissociated fractions were stimulated with a series of pulse frequencies of 3 Hz, time of 2 minutes, and 30 mA current for 3 minutes. The test drug was added from the eighth dissolution to the end of the experiment. The first current (or K +) stimulation results in a standard amount of [3h] 5-HT release (S). When the h5_HT1B antagonist was added to the medium between the first and second current stimulation, the release amount (S2) during the second stimulation effect increased with increasing dose. The svSi ratio is the percentage of [3η] 5_ HT released from the second stimulus divided by the percentage of [3H] 5-HT (SJ) released from the first stimulus. It is used to settle the effect of the drug on the release of precursors. See Figure 1. (ii) Metabolic rate of 5-HT in vivo · Combination method of 1-5-HT1B antagonist and 5-HTi A dry antagonist Compound A is a potent and selective h5-HT! B receptor antagonist, Compound B is a potent and selective 5-HT1A receptor antagonist. This experiment explores different doses of Compound A (2.8 and 40 μmol / y, v kg sc) and a fixed dose of Compound B (1 μmol The combination of ear / kg sc ·) is $ -73 in four different brain regions (inferior hypothalamus, hippocampus, striatum, and forebrain cortex). This paper size applies the Chinese National Standard (CNS) Α4 specification (210X297). Li) (Please read the back of the page first: Matters of interest_then fill in this page;} Yi,-= 口 568786 Member of the Central Standards Bureau of the Ministry of Economics. Printed by A-B7 of T-Consumer Cooperatives V. Description of the invention (71) Wei Ji Θ The effect of the ratio of BUDO acetic acid (5_HIAA) / 5_HT concentration. 5_ light base 4 丨 indoacetic acid; the change in the ratio of (5-HIAA) to 5-HT indicates the change in 5-HT metabolism. Each group Five guinea pigs (Harland (Winkelmann, Germany), each weighing 350-400 grams, were administered subcutaneously with compound A (2 hours) and compound B (1 hour), respectively, and then the animals were killed. They were quickly dissected and examined for inspection The brain was frozen on dry ice and stored at -70 ° C until analysis. A 10-fold volume (w / v) containing 5.0 mM sodium bisulfite i.〇mMEDTA, and 2 μΜ as internal standards of the isoproterenol Extraction of 5-ΗΤ and its metabolite 5-ΗΙΑΑ from a fixed weight of brain tissue with 〇 · ιμ peroxyacid. After centrifugation (14,000 xg for 10 minutes, 4 ° C), the supernatant solution (50 μl) was directly injected into Supelcosil LC-18_DB (3 mm) on-column column detector (esa Coulochemll), set 0.05 / 0.35 V. The mobile phase is 01 μ phosphonate buffer (pH 2.5): methanol-10: 90 ν / ν, Which contains 1 mM octyl sulfate. Figure 2 shows the combination of compound A and compound B compared with the result of compound A alone, which shows that the former has an enhanced effect on 5-HT metabolism. 0 Compound A: (R) -N- [5-methyl · 8- (4 • methylhexahydro p-pyridyl-3 4_tetrahydro-2-amidino] -4-morpholinophenamine compound B: (R) -3-N, N-Diamyobutyl-8-dun-3,4-dihydro-2Η-1_benzene 幷 ρ-furan-5-chitamine- (2R, 3R) -tartaric acid Salt monohydrate (please read the A meaning on the back ^ before filling out this page) 衣 、-口 -74-

Claims (1)

56¾% δ C8 D8 Patent Application No. 087U4345 Chinese Patent Application Replacement (June 1992) Patent Application Scope. A combination for the treatment of emotional disorders, the first component (a) of which is the choice of formula I Sexual 5-HT1 / V antagonists: (D where n is propyl or cyclobutyl, trans 2 is isopropyl, third butyl, cyclobutyl, cyclopentyl, or cyclohexyl, r3 is hydrogen and r4 is hydrogen or methyl, and is (R) · Enantiomer, its second component (b) is a selective h5-HT 丨 b junction antagonist or partial agonist such as formula π C is NIR (Π) ο The size of this paper is applicable to China National Standard (CNS) A4 (210 X 297 mm) 568786 Λ 8 m C8 08 κ, the patent application garden Y is CONH, NHCO; 1 is H, base. 3-0: 6 ring alkyl; 112 is fluorene, C "C6 alkyl, C" C6 alkoxy, halogen; R3 is o-cf3 -c (o) nr4r5; R4 and R5 are η or C "C4 alkyl, respectively, which are racemates, R-enantiomers or S-enantiomers, and this component ( a) and (b) are in the form of free base or a pharmaceutically acceptable salt thereof, wherein the subcutaneous administration ratio of the component (a) to the component (b) ranges from 1 to 50: 1 micromole / kg. The first combination of the scope of the patent application 'wherein the first component (a) is a compound selected from the following: (R) -3- (N-cyclopentyl-N-n-propylamino) · 8-fluoro-5- Methylaminocarbamyl-3,4-dihydro-2Η-1-benzopyran, (R) -8-gas-3- (N-isopropyl-N-n-propylamino) -5-amine Methylmethyl-3,4-dihydro-2fluorene-1-benzopyran, (R) -5-aminomethylmethylmethyl 3- (N-third butyl · N-n-propylamino) -8 · Fluorine, 3,4_ Diphosphine-2Η-1 · benzoρbiran '(R) -5-aminomethylamidino-3- (N-cyclobutylpropylamino) -8-fluoro-3,4-di Qi-2Η-1-benzopyran, (R) -5-aminomethylmethyl · 3- (N-cyclobutyl-N-isopropylamino) -8-fluoro-3,4 · erf-2 Η -1 · Benzophane, -2- This paper uses Chinese National Standards (CNS) Α4 size < 210 X 297 mm) Λ Η ΒΗ C8 568786- —_____— D8 VI. Application ^ 范 ί— '— (R) -5-Aminomethylamidino_3_ (N-cyclopentyl-n-propylaminopropyl 8-fluoro_3,4 • digas-2 Η -1 -Benzopyran, & (R) -5-aminomethylamino-3 · (Icecyclohexyl small · n-diamino group 8 · Fluorine · 3,4 · Digas " * 2 Η -1 -Benzopyran, & (R) -5-Aminomethylamido-3 · (fluorenylcyclopentyl-sylcyclobutylamino) · 8 · fluoro · 3,4_dioxo-2 Η -1 -Benzo benzopyran, wherein the compound is in the form of a free base or a pharmaceutically acceptable salt thereof. 3. According to the combination of item i in the patent application scope, wherein the first component ⑷ is compound (R) -5- Aminomethyl-3- (N, fluorene dicyclobutylamino 8-fluoro ", 4 · dihydro · 2H-1-benzopyran, which is in the form of a free base or a pharmaceutically acceptable salt thereof 4. The combination according to item 丨 of the scope of the patent application, wherein the second component (b) is a compound of formula II, where X is CH2. 5. The combination according to the scope of the patent application, item 4, wherein the second component (B) is a compound of formula II, wherein γ is NHCO. 6. According to the combination of item 5 in the scope of the applied patent, wherein the second component (b) is a compound of formula II, Where r3 is morpholinyl. 7. According to the combination of item 1 in the scope of the applied patent, wherein the second component (b) is a compound of formula II, wherein h is hydrogen, methyl or ethyl and R2 is hydrogen, methyl , Ethyl, methoxy or bromine. 8. The combination according to item 1 of the scope of patent application, wherein the second component (b) is a compound selected from the group consisting of: (R) -N- [M hexahydropyrine-1-yl) -1, 2, 3,4-tetrahydro-2-fluorenyl] -4-morpholinazidine; (R) -N- [8- (4-ethylhexahydropyrimidin-1-yl) -1,2,3 , 4-tetra argon-2-tea-based_ -3- This paper is selected from Chinese National Standards < CNS) A4 size (210X297 mm) Hold 568786 AS B8 C8 D8 Scope of patent application] -4 -Merbenilamine; (R) -N- [8- (4-methylhexahydropyridin-1-yl) -1,2,3,4- Tetrahydro-2-fluorenyl] -4 -morphinophenamine; (R) -N- [5 -methoxy-8- (4-methylhexahydropyridin-1-yl) -1,2 , 3,4-tetrahydro-2-fluorenyl] -4-morpholinobenzamide; (R) -N- [5-ethyl-8- (4-methylhexahydropyrimidin-1-yl) -1,2,3,4-tetrahydro • 2-fluorenyl] -4-morpholinobenzamide; (R) -N- [5-ethyl-8- (4-methylhexahydropyridine- 1-yl) -1,2,3,4-tetrahydro--2-fluorenyl]-(4-morpholinecarbonyl) benzidine; (R) -N- [5-methoxy-8- ( 4-methylhexahydropyridin-1-yl) -1,2,3,4-tetraaza-2-naphthyl] -4 -morpholinyl benzylamine; (R) -N- [5- Bromo-8- (hexahydropyridin-1-yl) -1,2,3,4-tetrahydro-2-fluorenyl] -4 -morphinophenamine; 1 ^-[5- > 8- (4-methyl-7? Nitro "7-Biehu-1-yl) -1,2,3,4-tetraaza-2-naphthyl] -4-morpholinobenzine; (R) -N -[5-bromo-8- (4-methylhexahydropyridin-1-yl) -1,2,3,4-tetrahydro-2-fluorenyl] -4-trifluoromethylbenzidine; (R) -N- [5-methyl-8- (4-methylhexahydropyridin-1-yl) -1,2,3,4-tetrahydro-2 -nayl] -4 -morphine Benzene 8] | amine, -N- (4-morpholinylphenyl) -8- (4 -Methylhexahydropyridyl) · 5 · methoxy-1,2,3,4-tetrazolidine-2-fermentamine; (R) -N- (4-morpholinyl) -8 -(4-methylhexahydropyridyl) -5-methoxy-1,2,3,4-tetrahydrofluorene-2-carboxamide; (S) -N- (4-morpholinylphenyl ) -8- (4-methylhexahydropyridyl) -5 -methoxy-4 This paper is based on Chinese national standards < CNS) A4 specifications < 21〇x 297 mm) 568786 Ί2,3,4-tetrahydrofluorene-2-carboxamide; (R) -N- (morpholinecarbonylphenyl) -8- (4-methylhexahydropyridine · boxy) · 5 · methoxy 1,2,3,4-tetrahydrofluorene-2-carboxamidine; (S) -N- [5- (4-methylhexahydropyridine q-yl) _3,4-dihydro · 2Η -1 • Benzopyran-3-yl] -4-morpholinobenzine; (S) -N- [5- (4-methylhexahydropyridine. Butyl) -3, 'dihydro Benzene-3-yl] -4- (4-hexahydropyridone-1-yl) benzidine; (S) -N- [8-methyl-5- (4-methylhexahydro Pyridine, well + group) _3,4 · dihydro • 2H-1-benzopyran-3-yl] -4- (dimethylaminecarbonyl) benzidine; N- [4- (4-morpholinyl ) Phenyl] -8-methoxy · 5 · ('methyl-hexapyridine + yl) -3,4-dihydro-2Η-1-benzopyran,% chloramine; wherein the compound It is in the form of a free base or a pharmaceutically acceptable salt thereof. 9. The combination according to item 8 of the patent claim, wherein the second component (b) is a compound selected from the group consisting of: (r) -N- [8- (4-methylhexahydropyridine) ， 2 3,4 · tetrahydro · 2 · naphthyl] -4 · morphine benzamidine; (R) -N- [5 · methoxyl (4-methylhexahydro yebujing small base 1 2 3 4 • Tetraargin-2-naphthyl] -4-morpholinobenzamide; and (R) -N- [5-methyl-8- (4-methylhexahydropyridine) Tetrahydro-2-fluorenyl] -4-morpholine benzidine. 10. The combination according to item 1 of the scope of the application for patent, wherein the component (&) is the compound fluoren-5-aminomethylfluorenyl-3- ( N, N-dicyclobutylamine-based gas · 3,4-dihydro-2Η-1 · benzopyran, and the component (b) is the compound (r) -n. [5-methyl-8- (4 -Methylhexahydropyridin-1-yl) -1,2,3,4-tetraargon-2-fluorenyl] -4-morpholine phenylhydrazone-5- This paper is applicable to countries and countries. ≪ CNS > A4 size (210X 297 mm) 568786 Λ 8 ns cs r) 8 Patented fenestram 'and the compound ("and ...") is in the form of a free base or a pharmaceutically acceptable salt thereof. U · According to the application The combination of any one of the patent fan park items i to 10, which is used to treat camp depression. A pharmaceutical composition for treating emotional disorders, wherein the active ingredient is a group defined in accordance with any one of the following patent scope # 丨 i 10 # as necessary with adjuvants, diluents, excipients, and or inert carriers Group 13. The pharmaceutical composition according to item 12 of the patent application is used for suppressing dysentery. 〇 According to the set of any of the patent application park κ 1Q-item set. Dan Department King 568786 No. 87114345 Specification of Chinese Patent Application for Patent Application (August 1990) Table 1: After oral administration (PO) and subcutaneous (SC) administration, the binding affinity (Ki) and the minimum effective dose of compound ⑷ to antagonistic 5-HT1A receptors. (a) Ki (nM) pre-synaptic 5-HT1A antagonistic SC / PO (mg / kg) i Synaptic «5-ΗΤ1Α antagonistic hippocampal SC / PO (mg / kg) aminino- 3- (7V; # -dicyclobutylamino) -8-fluoro-3,4-dihydro-2 //-1-benzopyran (Compound (B)) < 0.3 3 /-1/10 (/?)-3- (A ^ cyclopentyl-AL-n-propylamino) -8-gas-5-methylaminomethylmethyl-3,4-dihydro-2 //-1-benzo Pyran 1.76 3Λ 1/10 fluoroisopropyl-M-n-propylamino) -5-aminomethylamido-3,4-di -2 //-1-Fungo p ratio 5.45 1/3 0.01 / 1 (Λ) -5-aminomethylmethyl-3- (M third butyl n-propylamino) -8-fluoro-3 , 4-dihydro-2 //-1-benzopyran 1.07 1/10 0.03 / 1 〇R) -5-aminomethylmethyl-3- (7V-cyclobutyl-Mpropylamino)- 8-fluoro-3,4-dihydro-2 // small benzopyran 1.17 1/10 (Λ) -5-aminomethylamidino-3- (7V-cyclobutylisopropylamino) each fluorine -3,4 · dihydro-2 //-benzobenzopyran 1.75 1/10 0.03 / 3 dextranamine cyclopentyl-n-propylamino) each fluorine_3,4_dihydro-2 //-1-Benzopyran 1.5 3 /-0.1 / 1 ~ (Ry5-m T SS * -3- (iV-cyclohexyl-n-propylamino) -8-fluoro-3,4-dihydro- 2 //-1-Epi if pyran 2.53 methane-3- (7V-cyclopentyl-A «pyrimidine) -8-fluoro-3,4-dihydro-2 ///-1-benzo Pyran 1.52 1/10 Table 1 The results show that the compounds exemplified in this case have a high binding affinity for the 5 # 1 ^ receptor. These results further illustrate that all compounds, whether orally or subcutaneously, are administered before or after On touch readings, they are all effective. The method used to perform this combination test is as follows. Table 2. In vitro release of serotonin, which is expressed as the release of serotonin produced by two consecutive nerve stimulations after administration of compounds 浓度 at concentrations of 0.00, 0, and 1 Ratio d / S!%). Pyrogen-1-yl) -1 di 3,4-tetrakis, benzamidine ^ oxy-8: ^ 7 ^^ hexahydro | well tenyl)], 2,3,4_tetra-gas_2_ Phenyl] _4_ 《Say pyrimidinyl-h, 2,3,4-tetrabenzimidamine Inquiry P7 methoxy-t-pinyl hexahydro; Jing-1-yl) -1,2,3,4- (| ^ 2 ^: group 1_4- 嗔 ^ _ Method for conducting 5-HT1A receptor binding assay To evaluate the affinity for 5-HT1A-receptor, a test using a mouse brain as described below and measured Kr values shown in Table 1 are used. : The cerebral cortex and hippocampus were dissected from Sprague-Dawley mice, and in uitra-Turrax (15 ml of ice-cold 50 mM Tris-HC1 buffer containing 40 mM CaCU and 5.7 mM ascorbic acid (π buffer A "). ; Janke & Kunkel, Staufen, FRG) homogenized for 10 seconds. At 17,000 rpm (39,80xg), at a Beckman equipped with an ice-cooled JA-17 rotor, -2- 786786 (Beckman, Palo Alto, (CA, USA)). After centrifugation for 5 minutes, the pellets were resuspended in buffer A, and then homogenization and centrifugation were repeated. Each pellet was suspended in 5 liters of ice-cold 0.32 M Sucrose was then homogenized for 5 seconds. The homogenized sample maintained a cold rolling state of -70 ° C. When in use, the sample was diluted with buffer A to 8 mg tissue / ml, and then homogenized for 10 seconds. The tissue homogenization solution was cultured at 3 / t: 10 minutes, and then 10-pargyline was supplied therein, and then cultured for 10 minutes. Follow Peroutka, J. Neurochem. 47, 529-540, (1986 ) Perform the binding test in the manner described `` Basically this test is used to measure the inhibition of a given competitor molecule for 3h_8_〇. The ability of h_dpat to bind to 5-HT1a receptors. A culture mixture containing 3H_8_OH①PAT (.25 to 8 blessings), the desired child, the test (competitor) compound, and 5 mg / ml tissue homogenization (2 ml), put in 50 mM Tris-HCl buffer containing 4.0 mM CaCl2 and 5.7 mM ascorbic acid, pH 7.5. Analyze 3h_8_〇H-DPAT at six different concentrations by adding tissue homogenization solution and then Incubate for 10 minutes at 37 ° C to start binding experiments. The culture mixture is filtered through a Whatman GF / B glass filter (Gaithersburg, MD, USA) containing Brandel Cell Harvester, and the filter is 5 ml of ice-cold Tris-pH 7.5 Wash twice with HCl buffer and count in ultima Gold ™ (Packard) in a Beckman LS 3801 scintillation counter. Measure non-specific binding by adding 10 μM 5-HT to the reaction mixture. The binding data is non-linear Take square computer analysis (Munson and Rodbard, Anal. Biochem. 107, 220-239, (1980)). The data is expressed as Ki value (nM), which is determined by correcting the concentration of the ligand and its affinity constant. From IC5 Values calculated from. The IQo value refers to the concentration of a competitor / inhibitor molecule sufficient to bind and effectively block half of the receptor molecules. Individual & values for each given test compound were obtained as a result of two binding tests performed at 10 different concentrations. -3-